DDDC 2019 Organizing Committee

Conference Sponsors

2 Drug Discovery and Development Colloquium 2018 VI Annual Conference June 13 - 15, 2019

Skylar Connor, Conference Co-chair, Shraddha Thakkar, Ph.D., Conference Co-chair, UAMS AAPS Student Chapter President, Student UAMS AAPS Student Chapter Sponsor, Faculty University of Arkansas for Medical Sciences • FDA National Center for Toxicological Research University of Arkansas Little Rock Ujwani Nukala, Organizing Committee, UAMS Cesar M. Compadre, Ph.D., Conference Co-chair, AAPS Student Chapter Past-President, Student UAMS AAPS Student Chapter Co-Sponsor, University of Arkansas for Medical Sciences Faculty University of Arkansas Little Rock University of Arkansas for Medical Sciences Ting Lee, Organizing Committee, UAMS AAPS David Mery, Organizing Committee, UAMS Student Chapter Treasurer, Student AAPS Student Chapter Chair Elect, Student University of Arkansas for Medical Sciences. University of Arkansas for Medical Sciences University of Arkansas Little Rock Cord Carter, Organizing Committee, UAMS AAPS Pankaj Patyal, Organizing Committee, UAMS Student Chapter Secretary, Student AAPS Student Chapter Vice President, Student University of Arkansas for Medical Sciences University of Arkansas for Medical Sciences Taylor Connor, Organizing Committee, UAMS Nemu Saumyadip, Organizing Committee, AAPS Student Chapter Member, Student UAMS AAPS Student Chapter Member, Student University of Arkansas for Medical Sciences University of Arkansas for Medical Sciences Phuc Tran, Organizing Committee, UAMS AAPS Edward Selvik, Organizing Committee, UAMS Student Chapter Member, Student AAPS Student Chapter Member, Student University of Arkansas for Medical Sciences University of Arkansas for Medical Sciences University of Arkansas Little Rock

Table of Contents

DDDC 2019 Agenda 5 List of Poster Presenters 10 Speakers and Organizers Bios 11 Abstracts 23

3 Drug Discovery and Development Colloquium 2019 University of Arkansas for Medical Sciences I. Dodd Wilson Education Building Day 1, Thursday June 13, 2019 2:00-7:00 pm Registration Welcome and Opening Remarks Schwanda Flowers, Pharm.D. Interim Dean, Associate Dean for Administrative and Academic Affairs. Associate Professor, Pharmacy Practice 4:00-4:05 pm Dean Robert E. McGehee, Jr., Ph.D. Dean, UAMS Graduate School, Executive Director, Arkansas Biosciences Institute Professor, Department of Pediatrics/Neonatology, UAMS College of Medicine and Ark. Children's Hospital Keynote Presentation Artificial Intelligences and Machine Learning for Genomics and Biomarkers 4:05-4:55 pm Weida Tong, Ph.D. Director, Division of Bioinformatics and Biostatistics, National Center for Toxicological Research at US FDA 4:55-5:00 pm Break Session 1 Session Chair: Ujwani Nukahla, Graduate Student, University of Arkansas for Medical Sciences Edward Selvik, Graduate Student, University of Arkansas for Medical Sciences FDALabel Database on Amazon Cloud with Rich Drug Labeling Information to Advance the Application of Precision Medicine 5:00 – 5:20 pm Hong Fang, Ph.D. Senior Bioinformatician, Office of Scientific co-ordination, National Center for Toxicological Research at US FDA (Abstract no 41/ Page 63) Synthesis, In Vitro Stability And In vivo Pharmacokinetic Behavior of Opioid-Cannabinoid Codrugs as Potential Nociceptive and Neuropathic Pain Agents

5:20 – 5:35 pm Zaineb Albayati, Ph.D. Research Associate II, University of Arkansas for Medical Sciences (Abstract no 2/ Page24) Development and Validation of Estrogen Receptor Beta Binding Prediction Model Using Large Sets of Chemicals

5:35 – 5:50 pm Suguna Devi Sakkiah, Ph.D. Visiting Scientist, National Center for Toxicological Research at US FDA (Abstract no 38/ Page 60)

5:50 -7:30 pm Poster Session and Student-Faculty Mixer Day 2, Friday June 14, 2019 7:30-8:00 am Coffee and Light Breakfast 8:00-12:00 am Registration Sunrise Session Pharmacokinetics in Drug Development and Discovery 8:00-9:00 am Philip J. Breen, Ph.D. Professor, Collage of Pharmacy, University of Arkansas for Medical Sciences Keynote Presentation Biomarker Science in Monitoring Drug Safety and Disease State 9:00-9:50 am Vishal Vaidya, Ph.D. Director, Biomarker Analytics Global Lead at Pfizer 9:50- 10:00 am Break Session 2 Session Chair: Ting Li, Graduate Student, National Center for Toxicological Research at US FDA David Mery, Graduate Student, University of Arkansas for Medical Sciences Featured Speaker Discovering drugs from nature: Accurate calculations and experiments to help determine the structure and properties of complex, flexible natural products.

10:00-10:30 am Robert Doerksen, Ph.D. Associate Dean of the Graduate School, Associate Professor of Medicinal Chemistry, Research Associate Professor in the Research Institute of Pharmaceutical Sciences, University of Mississippi Drug Repositioning for Noonan and LEOPARD Syndrome by Integrating Transcriptomics and Structure-based Approach 10:30-10:45 am Liyuan Zhu Graduate Student, National Center for Toxicological Research (Abstract no 40/ Page 62) Activation of Metabolic Space of Cystobacter Ferrugineus by Intercepting

10:45-11:00 am Shukria Akbar Graduate Student, University of Mississippi (Abstract no 29/ Page 51) Bioactivation of Halogenated Aromatic Drugs as A Precursor to Drug-Induced Hepatotoxicity

11:00-11:15 am Mary "Allie" Davis Graduate Student, Collage of Pharmacology and Toxicology, University of Arkansas for Medical Sciences (Abstract no 12/ Page 34)

The Role of Non-Coding RNA and mRNA Interations In Regulation of Drug Metabolizing Enzymes and Hepatotoxicity

11:15 – 11:30 pm Dongying Li, Ph.D. Post-Doctoral Fellow, University of Arkansas for Medical Sciences (Abstract no 34/ Page 56) 11:30 - 12:15 pm Lunch Session 3 Session Chair: Phuc Tran, Graduate Student, University of Arkansas for Medical Sciences Cord Carter, Graduate Student, University of Arkansas for Medical Sciences Featured Speaker Plasma exosomal CYP2E1 and its role in neurotoxicity 12:15 – 12:45 pm Santosh Kumar, Ph.D. Associate Professor, Pharmaceutical Sciences, University of Tennessee Health Science Center 12:45 – 1:00 pm Break Keynote Presentation Improving Prediction: What Research Is Necessary to Enhance Drug Safety? 1:00-1:45 pm William Slikker, Jr., Ph.D. Director, National Center for Toxicological Research at US FDA Identification of Novel Drugs for Treatment of Neurodegenerative Diseases by Quantitative Structure-Activity Relationship Approach 1:45-2:15 pm Samuel Kakraba Graduate Student, University of Arkansas for Medical Sciences (Abstract no 33/ Page 55) Robust Liquid Chromatography Tandem Mass Spectrometry Method to Simultaneously Quantify Phytosterols and Tocopherols Entrapped in Liposomal Formulation 2:15-3:00 pm Asmita Poudel Graduate Student, University of Saskatchewan, Canada (Abstract no 36/ Page 58) 3:00 – 3:15 pm Break Session 4 Session Chair: Skylar Connor, Graduate Student, University of Arkansas for Medical Sciences Taylor Connor, Graduate Student, University of Arkansas for Medical Sciences Featured Speaker What Can We Learn from Millions of Viral Genome Sequences? 3:15 -3:45 pm David Ussery, Ph.D. Professor, Biomedical Informatics Department, Physiology and Biophysics Department in the College of Medicine, University of Arkansas for Medical Sciences, Director, Arkansas Center for Ecological and Genomic Medicine (ArC-GEM)

Anti-Metastatic Capacities of Melatonin Receptor Agonists on Different Breast Cancer Cell Lines 3:45-4:00 pm Alev Tascioglu Aliyev Graduate Student, University of Arkansas for Medical Sciences (Abstract no 31/ Page 53) Insights into The Dfg-Flip and Mechanism of Activation of Aurora Kinase B by Metadynamics 4:00-4:15 pm Naga Rajiv Lakkaniga Graduate Student, University of Arkansas for Medical Sciences (Abstract no 16/ Page 38) Develop a Database of Herbal/ Dietary Supplements (HDS) Hepatotoxicity for Supporting the FDA’s New Efforts to Strengthen Regulation of HDS Products

4:15-4:35 pm Minjun Chen, Ph.D. Principal Investigator, Division of Bioinformatics, National Center for Toxicological Research at US FDA (Abstract no 39/ Page 61) 4:35-4:45 pm Break Panel Discussion Drug Discovery and Development in an Academic Environment Moderator: Shraddha Thakkar Ph.D., Principal Investigator, National Center for Toxicological Research, at US FDA Panelist: 4:45-5:45 pm Cesar Compadre Ph.D., Professor, University of Arkansas for Medical Sciences James Sumpter Ph.D., Managing Director at Caerul LLC Darin Jones Ph.D., Associate Professor, University of Arkansas for Medical Sciences Pravin R. Chaturvedi, Ph.D., CEO, Oceanyx Pharmaceuticals Weida Tong, Ph.D., Director, Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, at US FDA Day 3, Saturday June 15, 2019 7:30-8:00 am Coffee and Light Breakfast Sunrise Session Career Development 8:00-9:00 am (CV & LinkedIn Tips & Help, Post Doctorial Panels) (Faculty only Round Table) Keynote Presentation Practical Considerations in Development of New Drugs from Natural Product Initiatives 9:00-9:45 am Pravin Chaturvedi, Ph.D. CEO, Oceanyx Pharmaceuticals 9:45-10:00 am Break Session 5 Session Chair: Julia Tobacyk, Graduate Student, University of Arkansas for Medical Sciences

Featured Speaker The olive-based (-)-oleocanthal as a novel target-based breast cancer recurrence inhibitor 10:00-10:30 am Khalid El Sayed, Ph.D. Professor of Medicinal and Natural Products, Chemistry, University of Louisiana, Monaro Featured Speaker Evidence for a novel mechanism of action for anticancer 1,2,4-thiadiazolidin-3,5-dione derivatives 10:30-11:00 am Peter Crooks, Ph.D. Professor and Chairman Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences 11:00-11:15 am Break Antioxidant Tocols As Potent Radiation Countermeasures

11:15-11:30 am Ujwani Nukala Graduate Student, University of Arkansas for Medical Sciences (Abstract no 35/ Page 57) Anti-Inflammatory Effect of Selective Cb2 Inverse Agonists in Murine and Human Microglial Cells

11:00-11:15 am Sahar Alghamdi Graduate Student, University of Tennessee Health Science Center (Abstract no 3/ Page 25) Species Identification of Food Contaminating Beetles Through Elytral Pattern Analysis

11:45 – 12:00 pm Tanmay Bera, Ph.D. ORISE Fellow, National Center for Toxicological Research (Abstract no 32/ Page 54) Engineering 89Zr-Labeled Amino Acid Functionalized Diamond Nanoparticles for Gene Delivery: Method Development, Optimization, Stability Study and Biodistribution Studies 12:00 – 12:15 pm Raj Rai Graduate Student, University of Shakshukan, Canada (Abstract no 37/ Page 59) Lunch and Awards Ceremony & Closing Remarks 12:15 -1:30 am Shraddha Thakkar Ph.D., Principal Investigator, National Center for Toxicological Research, at US FDA

List of DDDC 2019 Poster Presenters

Poster First Name Last Name Institution Number

Ayooluwa Aderibigbe The University of Mississippi 1

Zaineb Albayati University of Arkansas for Medical Sciences 2

Sahar Alghamdi University of Tennessee Health Sciences Center 3

Karsten Amezcua University of Arkansas for Medical Sciences 4

Dustyn Barnette University of Arkansas for Medical Sciences 5

Pan Bohu National Center for Toxicological Research 6

Shobanbabu Bommagani University of Arkansas for Medical Sciences 7

Suresh Bowroju University of Arkansas for Medical Sciences 8

Cord Carter University of Arkansas for Medical Sciences 9

Skylar Connor University of Arkansas for Medical Sciences 10

Soma Dachavaram University of Arkansas for Medical Sciences 11

Mary Davis University of Arkansas for Medical Sciences 12

Nathaniel Hill National Center for Toxicological Research 13

Venumadhav Janganati University of Arkansas for Medical Sciences 14

Anupreet Kharbanda University of Arkansas for Medical Sciences 15

Naga Rajiv Lakkaniga University of Arkansas for Medical Sciences 16

Ting Li UALR/UAMS/NCTR 17

David Mery University of Arkansas for Medical Sciences 18

Xiaoxu Na University of Arkansas at Little Rock 19

Pankaj Patyal University of Arkansas for Medical Sciences 20

Narsimha Penthala University of Arkansas for Medical Sciences 21

Debasmita Saha University of Arkansas for Medical Sciences 22

Julia Tobacyk University of Arkansas for Medical Sciences 23

Alicja Urbaniak University of Arkansas for Medical Sciences 24

Jedidiah Whitt Arkansas State University, Jonesboro 25

Matthew Windsor University of Arkansas for Medical Sciences 26

Leihong Wu National Center for Toxicological Research 27

Wei Zhuang National Center for Toxicological Research 28

Anthony Sumlin University of Mississippi 30

Keynote Speakers

Weida Tong, Ph.D. Director, Division of Bioinformatics and Biostatistics, National Center for Toxicological Research Dr. Tong is Director of Division of Bioinformatics and Biostatistics at FDA’s National Center for Toxicological Research (NCTR/FDA). He has served a science advisory board member for several large projects involving multiple institutes in Europe and USA. He also holds several adjunct positions at universities in the US and China. His division at FDA works to develop bioinformatic methodologies and standards to support FDA research and regulation and to advance regulatory science and personalized medicine. The most visible projects of his group are (1) leading the Microarray Quality Control (MAQC) consortium to develop standard analysis protocols and quality control metrics for emerging technologies to support regulatory science and precision medicine; (2) development of liver toxicity knowledge base (LTKB) for drug safety; (3) in silico drug repositioning for the enhanced treatment of rare diseases; and (4) development of the FDA bioinformatics system, ArrayTrackTM suite, to support FDA review and research on pharmacogenomics. In addition, his group also specializes in molecular modeling and QSARs with a specific interest in estrogen, androgen, and endocrine disruptor. Dr. Tong has published more than 230 papers and book chapters.

Vishal Vaidya, Ph.D. Global Head of Biomarker Analytics Laboratory in Drug Safety Research and Development at Pfizer, Inc. Dr. Vaidya is the Global Head of Biomarker Analytics Laboratory in Drug Safety Research and Development at Pfizer, Inc. He is also an Associate Professor at Brigham and Women’s Hospital, Harvard Medical School. Vishal has led multidisciplinary teams in academe and industry with a goal of impacting patients’ lives by discovering disease-modulating targets and disease monitoring biomarkers. His team at Pfizer supports medicine development across all therapeutic areas to increase confidence in non-clinical safety & to provide clinical safety monitoring strategies by discovering, validating and implementing translational biomarkers. Vishal’s team at Harvard conducted innovative translational research to predict, prevent and treat kidney disease. He has been a recipient of NIH/NIEHS Outstanding New Environmental Scientist Award, Burroughs Wellcome Fund’s Innovation in Regulatory Science Award, Society of Toxicology’s (SOT) Leading Edge in Basic Science Award and the SOT Achievement Award. Vishal is elected as a fellow of the Academy of Toxicological Sciences.

William Slikker, Jr., Ph.D. Director, National Center for Toxicological Research at US FDA Dr. Slikker received his Ph.D. in pharmacology and toxicology from the University of California at Davis. He performed his postdoctoral training in the Perinatal Research Program at FDA’s National Center for Toxicological Research and at the Institute of Toxicology and Embryopharmacology, Freie Universität, Berlin. Dr. Slikker holds adjunct professorships in the Department of Pediatrics and the Department of Pharmacology and Toxicology at the University of Arkansas for Medical Sciences. He has held leadership positions in several scientific societies including the Teratology Society, the MidSouth Computational Biology and Bioinformatics Society, the American Society for Pharmacology and Experimental Therapeutics, and the Society of Toxicology. Dr. Slikker has authored or co-authored over 300 publications in the areas of transplacental pharmacokinetics, developmental neurotoxicology, neuroprotection, systems biology, and risk assessment. Dr. Slikker is a co-founder of the International Conference on Neuroprotective Agents. He has served on national and international advisory panels including those for the Health and Environmental Sciences Institute/International Life Sciences Institute, the U.S. Environmental Protection Agency, the National Institutes of Health, the National Academy of Sciences, and the World Health Organization. Dr. Slikker is also an invited member of the Academy of Toxicological Sciences and Associate Editor for NeuroToxicology and Toxicological Sciences.

Pravin R. Chaturvedi, Ph.D. CEO, Oceanyx Pharmaceuticals Dr. Pravin Chaturvedi is an experienced drug developer and biotech entrepreneur. He is the Chairman of the Scientific Advisory Board for Napo Pharmaceuticals and also serves as the CEO and Director for IndUS and Oceanyx Pharmaceuticals, both of which he also cofounded. Previously, he has served as the President and CEO of Pivot Pharmaceuticals and Scion Pharmaceuticals. Prior to his role at Scion, he was the Head of Lead Evaluation at Vertex and was in Product Development groups at Alkermes and Parke-Davis/Warner-Lambert (Pfizer). Over his career, he has participated in the successful development of several new drugs for the treatment of CNS, viral and gastrointestinal disorders. In addition to the boards of IndUS and Oceanyx, Dr. Chaturvedi is also the Chairman of the Board of Cellanyx, a first-in-class live tumor biopsy phenotypic testing enterprise. He also serves as a board member for FuelEd Schools and Sindu Research Laboratories. He has previously served on the boards of Pivot, Scion, Bach Pharma, PRADAN USA, Sindu Pharmaceuticals and TiE Boston. He also serves on several advisory boards including Enlivity and MAG Optics and is as an adjunct faculty member at Georgetown Medical School. He

12 holds a Ph.D. from West Virginia University and received his Bachelor’s in Pharmacy from the University of Bombay.

Featured Speakers Robert Doerksen, Ph.D. Associate Dean of the Graduate School, Associate Professor of Medicinal Chemistry and Research Associate Professor in the Research Institute of Pharmaceutical Sciences, University of Mississippi Robert J. Doerksen was born in Winnipeg, Manitoba, Canada and spent time growing up in Madison, Wisconsin, USA; Fredericton, New Brunswick, Canada; and Cambridge, England, UK. He obtained a Double First Class Honours Bachelor of Science in Mathematics and Physics from University of New Brunswick (UNB), a graduate level Diploma in Christian Studies from Regent College in Vancouver, British Columbia, Canada, and a PhD in Chemistry from UNB, under the guidance of Prof. Ajit Thakkar, specializing in computational physical chemistry. He proceeded to postdoctoral fellowships in the Department of Chemistry at University of California, Berkeley, with Prof. Martin Head-Gordon, and in the Department of Chemistry at University of Pennsylvania (Philadephia, PA, USA), with Prof. Michael Klein. Since 2004, he has been at the School of Pharmacy at the University of Mississippi in Oxford, MS, USA, first as an assistant professor in the Department of Medicinal Chemistry and currently as an associate professor of medicinal chemistry in the Department of BioMolecular Sciences. Doerksen also is a research associate professor in the Research Institute of Pharmaceutical Sciences at the University of Mississippi. In 2017, he was appointed as Associate Dean of the Graduate School.

Santosh Kumar, Ph.D. Associate Professor, Pharmaceutical Sciences, The University of Tennessee Health Science Center Dr. Kumar is an Associate Professor in Pharmaceutical Sciences and Assistant Dean (effective July 1) for “Scholarly Integration and Collaboration” at College of Pharmacy. He graduated from the Indian Institute of Technology (IIT)-Bombay, India. Dr. Kumar did his post-doctorate fellowship from the University of Missouri-Kansas City (UMKC) followed by joined as a junior faculty at the University of Texas Medical Branch. He then went back to UMKC as an Assistant Professor before coming to UTHSC in 2014. Dr. Kumar is trained as a biochemist and enzymologist with expertise in drug metabolism, HIV, and substance abuse. His laboratory works in the field of HIV/AIDS, neuroAIDS, and substance use/abuse, especially alcohol and smoking, which is funded by several NIH grants. In the past 10 years, Dr. Kumar’s group has published substantially in this field (>60 papers), with a total of ~95 papers. Dr. Kumar has mentored six graduate

13 students and three post-doctorate fellows along with numerous other trainees. Currently, he is mentoring three graduate students and one PDF. In addition to research, Dr. Kumar participate significantly in classroom teaching to both professional pharmacy students and graduate students. Dr. Kumar has been actively engaged in serving the Society on Neuroimmune Pharmacology, not only as a member, but also as Chair of “Early Career Investigator (ECI) Committee, as well as Secretary and President-elect of the society. As a result of his distinguished contributions to research, teaching, mentoring, and service, Dr. Kumar has received numerous awards and honors. In the past five years Dr. Kumar has received: 1) Mahatma Gandhi Pravasi (Non-resident Indian (NRI)) Samman (Honor) from NRI, India, 2) Teacher of the Year Award from UMKC-School of Pharmacy, 3) Distinguish Service Award from the Society on Neuroimmune Pharmacology, 4) Postdoctoral Fellow Outstanding Junior Mentoring Academy Award from the Post-doctorate Association, UTHSC, 5) Phi Delta Chi (PDC) “Professor of the Year Award” from UTHSC-College of Pharmacy (twice in 2018 and 2019), 6) UT Alumni Association “Outstanding Teacher Award”, from the University of Tennessee, and 7) The Student Government Association Executive Council (SGAEC) “Excellence in Teaching Award”, from the Graduate College, UTHSC.

David Ussery, Ph.D. Professor, Biomedical Informatics Department, Physiology and Biophysics Department in the College of Medicine, University of Arkansas for Medical Sciences, Director, Arkansas Center for Ecological and Genomic Medicine (ArC-GEM) David W. Ussery, Ph.D. is a Professor, and the Helen G. Adams and Arkansas Research Alliance Chair in Bioinformatics in the Department of BioMedical Informatics at UAMS. He has a strong background in computational genomics; in 2016 he moved seven people from his Comparative Genomics group at Oak Ridge National Labs to UAMS, to focus on high-throughput comparative genomics, using High Performance Computing methods to compare millions of genomes. He has published more than 200 papers on computational tools for comparative genomics, and successfully funded and supervised more than two-dozen Ph.D. students. His group is developing computational methods to substantially speed up genome comparisons, as well as integrating data, including genomics, ‘epigenomics’, and direct transcriptomics from third generation sequencing, as well as proteomics and metabolomics."

Khalid El Sayed, Ph.D. Professor of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Louisiana at Monroe Dr. El Sayed earned his master’s and doctoral degrees in natural products chemistry/ pharmacognosy from Mansoura University, Egypt. His postdoctoral training on marine natural products was at the University of Mississippi. Dr. El Sayed group is developing natural products for breast cancer control. Dr. El Sayed group’s most important direction is the anti-breast cancer activity of olive phenolics, specifically (-)-oleocanthal through targeting the c-Met receptor kinase. (-)-Oleocanthal recently validated by Dr. El Sayed group as an effective inhibitor of various breast cancer phenotypes locoregional recurrence. Dr. El Sayed published more than 145 papers, 5 book chapters and awarded 13 patents. He has been funded by the National Cancer Institute (NCI), Louisiana Board of Regents, and several other foundations. Dr. El Sayed served on some NCI study sections and is an editorial board member in Marine Drugs and Nutrients.

Peter Crooks, Ph.D. Professor, Chairman, Collage of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR Dr. Crooks is internationally recognized for his research and work in anticancer drug discovery, delivery, and development. He leads a research team to discover and develop new cancer treatment drugs with an emphasis on lymphoma and leukemia; to develop radiation agents to improve patient outcomes after radiation therapy; and to develop new pain medication to treat acute and chronic pain. He also has an active program in drug abuse which focuses on the development of new treatments for methamphetamine, nicotine and alcohol addictions. Dr. Crooks has graduated 30 PhD students and 9 MS students, and trained over 60 postdoctoral fellows and visiting scientists. Dr. Crooks has also established or cofounded six drug discovery companies and his drug discovery patents and patent applications total more than 270. At present, several of his laboratory’s drugs are in various phases of clinical development. In September of 2013 the anti-cancer topical gel Valchlor, developed in Dr. Crook’s laboratories, was approved by the FDA for treatment of early-stage cutaneous T-cell lymphoma. In 2011, Dr. Crooks joined UAMS College of Pharmacy as Chairman and Professor of the Department of Pharmaceutical Sciences. He also holds the UAMS Simmons Endowed Chair in Cancer Research. Prior to Joining UAMS, Dr. Crooks held a joint faculty appointment at the University of Kentucky in the Graduate Center for Toxicology and the College of Pharmacy, as the George A. Digenis Professor in Drug Design and Discovery. Dr. Crooks received his bachelor’s degree (Hons) First Class in Pharmacy (1966); Master of Science in Pharmacy (1967); Ph.D. in Pharmacy, and Doctor of Science all from the University of Manchester, U.K. He was a faculty member in the

Department of Pharmacy, University of Manchester from 1968 to 1981. Dr. Crooks also spent two years as a research associate in the Department of Pharmacology, Sterling Hall of Medicine, Yale University (1976-1978)

Panelist & Workshops

Cesar M. Compadre, Ph.D. Conference Co-chair, Faculty, University of Arkansas for Medical Sciences Dr. Compadre is a professor at the Department of Pharmaceutical Sciences, of the University of Arkansas for Medical Sciences. He has extensive research experience on the development of bioactive compounds based on naturally occurring compounds, and on the use of molecular modeling in drug design and structure-activity studies. He has published over 90 papers and co-authored more than 70 patents related to the development of bioactive compounds. He is also the developer of one FDA approved antimicrobial technology, which is commercially used, and he is also co-founder of Tocol Pharmaceuticals, a company focused on the development of enhanced vitamin-E analogues. Dr. Compadre has extensive international research collaborations in drug Discovery, Global Health and Phytopharmaceuticals. Dr. Compadre has a BSPharm degree and obtained his Ph.D. degree in medicinal chemistry and pharmacognosy, from the University of Illinois at Chicago. He conducted postdoctoral research on structure-activity relationships studies using molecular modeling at the University of Illinois working with Dr. John M. Pezzuto and at Pomona College working with Professor Corwin Hansch. Additionally, he had a sabbatical experience at NASA Ames Research Center and computer modeling.

Shraddha Thakkar, Ph.D. Conference Co-chair, Principal Investigator, National Center for Toxicological Research, US Food and Drug Administration

Dr. Shraddha Thakkar received a master’s degree and Ph.D. in bioinformatics from the University of Arkansas at Little Rock/University of Arkansas Medical Sciences, Joint Bioinformatics program. She specialized in macromolecular crystallography, cheminformatics, and structural biology. Prior to that Dr. Thakkar received an MSc. in biotechnology from Bangalore University, India. She holds 14 international patents and multiple publications in area of drug development for radiation protection, predictive toxicology, leukemia, and atherosclerosis. Her current area of research includes development of methods and classifications to enhance the understanding and prediction of drug-induced liver injury (DILI).

Dr. Thakkar has adjunct appointments at both the University of Arkansas for Medical Sciences and the University Arkansas at Little Rock (Assistant Professor). She was elected as board

16 member of the Mid-South Computational Biology and Bioinformatics Society (MCBIOS) in 2014 and served as president of MCBIOS from 2016-2017. She also served as the chair of 1) Pharmacogenomics Group of the American Association of Pharmaceutical Scientist (AAPS) and 2) Personalized Medicine community at AAPS. Dr. Thakkar has received multiple research and leadership awards regionally and nationally and within FDA including the AAPS “Genentech Innovation in Biotechnology Award,” the American Crystallography Association’s “Margret C. Etter Student Lecturer Award,” and FDA’s “Outstanding Service Award.”

Darin Jones, Ph.D. Associate Professor, University of Arkansas for Medical Sciences Dr. Darin Jones is an associate professor the University of Arkansas for Medical Sciences. His research primarily focuses on medicinal chemistry and chemical biology. One of Jones’ research projects focuses on Acute Myelogenous Leukemia, which causes white blood cell precursors (myeloid cells) to divide uncontrollably. These abnormal cells eventually overcrowd red blood cells, normal white blood cells, and platelets. Jones and his researchers have discovered that the dehydroleucodine molecule–found in an ornamental shrub naturally grown in Ecuador–can help treat AML and related diseases. This project received national attention after Jones received a $50,000 grant from the Arkansas Science and Technology Authority. Another of Jones’ research projects on DNA repair processes was awarded a National Cancer Institute/National Institute of Health R01 research grant. Darin and his research team developed two unique classes of compounds that selectively kill cancer cells with little to no effect on non-cancerous cells. Jones has also been awarded numerous grants as principal investigator or co-principal investigator. He has collaborated on grants with faculty from various institutions such as Harvard, Yale, Cornell, University of California-Berkeley, the University of Montreal, and the Ulsan National Institute of Science and Technology, just to name a few. In total, he has received over $16 million dollars as either principal or co-principal investigator. Jones’ extensive body of work includes more than 40 books, patents, and prestigious research journals. Jones received a Ph.D. in Chemistry from the University of Missouri and a bachelor’s degree in Chemistry from Central Missouri State University.

James A. Sumpter, Ph.D. Managing Director at Caerul LLC Dr. James A. Sumpter is an interdisciplinary research and information scientist with over 20 years of experience specializing in cross-disciplinary project management and execution. Dr. Sumpter leverages his expertise in the application of a broad range of technical leadership, analytical methods, computational techniques, software engineering and mathematical modeling. He has a background in computer simulations and modeling, including machine learning, finite element analysis, computational fluid dynamics, engineering and statistical mechanics, model- based systems engineering, software development and project management. He applies innovative and creative ideas and methodologies to deliver practical solutions and is experienced leading and supporting teams and organizations from local to multi-national scale.

Brendan Frett, Ph.D. Assistant Professor of Pharmaceutical Sciences in the College of Pharmacy at the University of Arkansas for Medical Sciences Brendan Frett, Ph.D. is an Assistant Professor of Pharmaceutical Sciences in the College of Pharmacy at the University of Arkansas for Medical Sciences (UAMS). Dr. Frett received his Ph.D. degree in Pharmaceutical Sciences from the University of Arizona and completed postdoctoral studies in Pharmaceutics at the University of Arizona. Prior to joining UAMS in 2017, Dr. Frett served as the CEO of two start-up biotechnology companies, which focused on commercializing technologies discovered in an academic setting. One of the technologies is in the final stages of investigative new drug (IND) studies. At UAMS, Dr. Frett leads a team of medicinal chemists involved in the design, synthesis, and evaluation of small molecules for various therapeutic areas.

Organizing Committee and Student Moderators

Skylar Connor, Organizing Committee, Graduate Student University of Arkansas for Medical Sciences/ University of Arkansas Little Rock Skylar Connor is the Chair of the UAMS AAPS Student Chapter. She earned a Bachelor of Science Degree in Chemistry May 2015 and a Master of Science Degree in Computer Science May 2017 from the University of Arkansas at Pine Bluff. She is currently a third-year graduate student pursuing a Ph.D. in Bioinformatics in the joint Bioinformatics program at the University of Arkansas at Little Rock and University of Arkansas for Medical Sciences. Upon completion of her Doctorate she plans to use her bioinformatics background to advance the research of neurodegenerative diseases and viruses such as Alzheimer’s.

Ujwani Nukala, Organizing Committee, Graduate Student University of Arkansas for Medical Sciences /University of Arkansas Little Rock Ujwani Nukala is a Ph.D. Candidate in the Joint Bioinformatics Program from University of Arkansas at Little Rock (UALR)/University of Arkansas for Medical Sciences (UAMS). She received her MS degree in Bioinformatics from UALR/UAMS and M.Sc. in Biochemistry from Osmania University, India. Her research is focused on developing novel Vitamin E analogs as radiation protectors for use in accidental or terrorist initiated radiological emergencies through integrated computational-experimental studies. Ujwani has received multiple awards for her research and leadership roles including AAPS Biotechnology Graduate Student Research Award sponsored by Eli Lilly and Company, Young Scientist Excellence Award from MCBIOS, Excellence in Service Award and Outstanding Doctoral student Award from UALR. Ujwani is involved in various leadership activities in organizations including American Association of Pharmaceutical Scientists (AAPS), Regional Student Group (RSG) affiliated with International Society of Computational Biology and Bioinformatics Club at UAMS. She was elected as the board member (Student representative) of Mid- South Computational Biology and Bioinformatics Society (MCBIOS) in 2016.

Pankaj Patyal, Organizing Committee, Graduate Student University of Arkansas for Medical Sciences Pankaj Patyal holds vice-chair position at UAMS AAPS Student Chapter. He is a Ph.D candidate in the Department of Physiology and Biophysics at College of Medicine, University of Arkansas for Medical Sciences, where he furthers his research on the mechanisms that regulate myelin proteolipid protein gene (PLP1) expression in the nervous system in Dr. Patty Wight's laboratory. He has identified a critically important enhancer region in the intron1 of PLP1 and would like to test whether critical mutations in the enhancer could be the cause of pelizaeus-merzbacher disease in patients with unaltered PLP1 coding sequence and gene dosage. Pankaj's project will help to understand the etiology of the disease in the patients suffering with myelin degenerative neurological diseases. He is a member of American Society of Neurochemistry, presented his work in the annual meetings. He is also a member of Arkansas Chapter of the Society for Neuroscience. He has a bachelor’s degree in pharmacy from India and Masters degree in Pharmacology and Toxicology from Boonshoft college of Medicine, Wright State University, Ohio. He is also a member of Ohio Physiological Society and won Best Student Research poster-presentation award at the 29th Annual Meeting of the Ohio Physiological Society at Miami University. He also presented his Masters work in experimental biology meeting at San Diego.

David Mery, Organizing Committee, Graduate Student University of Arkansas for Medical Sciences

David Mery studied under Eloy Rodriguez while earning a Bachelor of Science in Biology from Cornell University. He is currently a graduate student pursuing a Ph.D. in Pharmaceutical Sciences at the University of Arkansas for Medical Sciences (UAMS). David is studying under the guidance of Dr. Cesar Compadre where they have been developing an innovative way to uncover natural products for leukemia from plants. His favorite part of research is trekking into untouched areas of the Midwest and Ecuador in search of flowers with unique medicinal compounds. Upon completion of his Doctorate he plans to use his background in natural products to pioneer new ways of studying medicinal plants.

Ting Li, Organizing Committee, Graduate Student University of Arkansas for Medical Sciences /University of Arkansas Little Rock Ting Li is a Ph.D. candidate in the Joint Bioinformatics Program from University of Arkansas at Little Rock (UALR) / University of Arkansas for Medical Sciences (UAMS). She received a Master of Science degree in Applied Mathematics from UALR and Bachelor of Science Degree in Computer Science from Hunan University, China. Her research interest focuses on predicting drug toxicity through machine learning and deep learning methods. She was also the Chair of the Regional Student Group at UALR.

Cord Carter, Organizing Committee, Graduate Student University of Arkansas for Medical Sciences Cord Carter is currently a third-year doctoral student in the Department of Pharmaceutical Sciences at the University of Arkansas for Medical Sciences College of Pharmacy. He received both his Bachelor of Science in Chemistry and Master of Science in Chemistry from Southeastern Oklahoma State University and Jackson State University respectively. He is currently serving as the Secretary/K-12 Liaison for the UAMS AAPS Student Chapter and recently elected as the 2019-2020 Graduate Student Association President. Under the mentorship of Drs. Cesar Compadre and Shraddha Thakkar, his research project is to develop a computational that can enhance the predictability of human drug-induced liver injury risk by using structure-based and biological descriptors. Upon graduation, he will then pursue a postdoctoral faculty fellowship position at an academic research lab with the goal of becoming a faculty member.

Taylor Connor, Organizing Committee, Graduate Student University of Arkansas for Medical Sciences Taylor Connor is currently a student in the Masters of Public Health Program at the University of Arkansas for Medical Sciences. She has been accepted and will start as a P1 in the College of Pharmacy Program here at the University in the Fall. Taylor received her Bachelor of Science Degree in Chemistry in May 2017 from the University of Arkansas at Pine Bluff. Upon completion of her Master’s and Doctorate of Pharmacy, Taylor plans to use the education gained for the advancement of the community.

Nemu Saumyadip, Organizing Committee, Graduate Student University of Arkansas at Little Rock/ University of Arkansas of Medical Science Saumyadip Nemu is a 3rdyear Chemistry PhD graduate student at the University of Arkansas at Little Rock (UALR) and also a visiting student of Department of Pharmacy at University of Arkansas of Medical Science (UAMS) working under Dr. Darin E. Jones. His research focus is on Design and Synthesis of Improved Inhibitors for DNA Ligases. He finished his Master’s in chemistry from Indian Institute of Technology, Bombay, India and Bachelor’s in Chemistry from Ramakrishna Mission Vidyamandira, Belur, India.

Phuc Tran, Organizing Committee, Graduate Student University of Arkansas of Medical Science Phuc Tran is a first year graduate student in Pharmaceutical Science at the University of Arkansas for Medical Science (UAMS). He received his B.S and M.S in Chemistry at University of Arkansas at Little Rock from 2012 to 2018. His research interest included application of machine learning and computational chemistry method in modern drug discovery. In additional, his current training were in organic synthesis of novel anti-melanoma agents. He is currently a member of AAPS (American Association of Pharmaceutical Scientist) at UAMS chapter.

University of Saskatchewan AAPS Student Chapter The University of Saskatchewan’s (UofS) Student Chapter of the American Association of Pharmaceutical Scientists (AAPS) was formed in early 2015. As a newer AAPS Student Chapter, we aim at creating a more coherent, diverse, social and scientific community at the University of Saskatchewan. This student chapter ideally connects students and postdoctoral fellows from different pharmaceutical backgrounds to the largest community of resources available for pharmaceutical discovery, development and manufacturing.

Our AAPS student chapter helps each student member to share knowledge with peers and mentors from a variety of field of studies such as biotechnology, clinical and epidemiological studies, pharmacology, toxicology, medicinal chemistry, analytical chemistry, pharmacokinetics, natural products and nutraceuticals, pharmaceutical quality as well as drug discovery and development, and pharmaceutics.

STUDENT AND POST-DOCTORAL ABSTRACTS

Student Poster 1

FINDING THE BINDING POCKET FOR ORG27569, A NEGATIVE ALLOSTERIC MODULATOR OF CANNABINOID RECEPTOR 1

AyoOluwa O. Aderibigbe1, Pankaj Pandey2, and Robert J. Doerksen*1,3

1Division of Medicinal Chemistry, Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS 38677 2National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS 38677 3Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677

Molecules that decrease CB1 receptor signaling have promising potential as pharmacotherapeutic agents in obesity management. Due to the adverse neuropsychiatric effects of the previously reported CNS-active antagonists and inverse agonists, there is an ongoing search for novel antagonists as anti-obesity agents. ORG27569, a negative allosteric modulator of the CB1 receptor, is known to increase the binding affinity of CP55940, a well-known orthosteric cannabinoid agonist, and to decrease the ligand efficacy of CP55940 in functional assays. ORG27569 also possesses an intrinsic inverse agonist effect on the CB1 receptor. There are no experimental 3D structures of the CB1 receptor bound to an allosteric modulator. Studies that have been performed to identify the allosteric binding site of ORG27569 report contradictory sites, so we aimed to resolve this.Here, we docked CP55940 into all four available X-ray crystal structures of the CB1 receptor using the Glide Standard Precision protocol. The docking protocol reproduced the binding poses of the native ligands in the active-state X-ray crystal structures with an RMSD < 1.0 Å for common atoms. A search for all possible allosteric sites within the four CP55940–bound CB1 structures affirmed the presence of multiple allosteric sites on the receptor. We ran a 50 ns molecular dynamics simulation on 5U09, an inactive-state CB1 structure, bound to CP55940. Binding site identification analysis performed on the MD trajectory revealed the presence of two predominant ‘binding site clusters’, one which overlapped with the well-known orthosteric site and a second at the intracellular end of the receptor. Docking of ORG27569 into both site clusters shows that the intracellular allosteric site is the preferred one, in agreement with a previous study and in contrast with a second study. This project is funded by R15-GM119061 from the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH). that the intracellular allosteric site is the preferred one, in agreement with a previous study and in contrast with a second study. This project is funded by R15-GM119061 from the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH).

Student Oral Presentation and Poster 2

SYNTHESIS, IN VITRO STABILITY AND IN VIVO PHARMACOKINETIC BEHAVIOR OF OPIOID-CANNABINOID CODRUGS AS POTENTIAL NOCICEPTIVE AND NEUROPATHIC PAIN AGENTS

Zaineb Albayati1, Harpreet Dhooper2, Philip J. Breen1 and Peter A. Crooks*1

1Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, 72205 2Department of Pharmaceutical Sceinces, University of Kentucky, Lexington, KY. 40536

A series of novel codrugs obtained by chemical conjugation of the opiate drug codeine with ∆9- THC, cannabidiol, and abn-cannabidiol, and of the opiate prodrug 3-O-acetylmorphine with ∆9- THC, utilizing a carbonate linker moiety, were successfully synthesized. The Cod-THC codrug was initially evaluated for its stability in buffers ranging from pH 1 to pH 9, as well as in simulated gastric and intestinal fluids, and in rat plasma and brain. The pharmacokinetic (PK) profile of the Cod-THC codrug and brain uptake were evaluated in the rat after oral administration and compared with those obtained after oral administration of an equimolar physical mixture of the two parent drugs, codeine and Δ9-THC. Results of the stability study of the Cod-THC codrug in different non-enzymatic aqueous buffers and in biological media demonstrate that the carbonate ester linkage of the codrug is predicted to be stable in the gastrointestinal tract when the codrug is administered orally. Hydrolytic studies of Cod-THC in 80% rat plasma indicate that the carbonate ester linkage is cleaved enzymatically to generate the two parent drugs, suggesting that after oral administration, and absorption from the gastrointestinal tract the codrug will generate both parent drugs in the systemic circulation. PK results show that the plasma concentrations of codeine and Δ9-THC were found to be much higher after oral administration of the codrug, compared to plasma concentrations of these drugs after oral administration of the physical mixture of the two parent drugs, indicating that more of parent drugs can be delivered orally in the form of the codrug than as a physical mixture. Moreover, the concentrations of codeine and Δ9-THC were much higher in brain after oral administration of the Cod-THC codrug as compared to brain concentrations of these drugs after oral administration of the physical mixture. The data clearly indicates improved PK results from a chemical combination of two synergistic drugs compared to those of a physical mixture of the two drugs.

Student Oral Presentation and Poster 3

ANTI-INFLAMMATORY EFFECT OF SELECTIVE CB2 INVERSE AGONISTS IN MURINE AND HUMAN MICROGLIAL CELLS

Sahar S. Alghamdi, Kirk E. Hevener, Bob M. Moore II*.

Department of Pharmaceutical Sciences, College of Pharmacy, the University of Tennessee Health Science Center, Memphis, TN.

Purpose: In the last 10 years, CB2 receptor has been emerged as a promising therapeutic target for treating multiple neurodegenerative disease (NDD) conditions such as Alzheimer’s (AD), Parkinson’s (PD), HIV and multiple sclerosis. CB2 receptors are predominantly expressed in the immune cells such as microglia, natural killer cells, B cells and macrophages with low or no detectible level in neurons in the central nervous system. During neuroinflammation, CB2 receptor expression is upregulated in microglial cells thus modulating the activated microglia can be a potential therapeutic approach for treating neurodegenerative diseases. When microglia cells are activated, the phenotype is changed from surveillance (M0) phenotype to an activated pro- inflammatory phenotype (M1) which contributes to increased inflammation and progression of neurodegenerative diseases. Selective CB2 inverse agonists can serve as novel anti-inflammatory therapeutics by switching the microglial cell neurotoxic M1 phenotype to an M2 pro-healing neuroprotective effect phenotype which is the key step in modulating the neuroinflammatory process. Results/Discussion: Compounds 231 and 97 triggered a shift in murine and human microglia polarization from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype after 24 hours. The M1 markers were significantly decreased and M2 markers significantly increased compared to LPS after drug treatment. In addition, 97 and 231 increased JNK, c-JUN, CREB and p38 levels and decreased ERK1/2 and NFκB representing a unique anti-inflammatory mechanism of CB2 inverse agonists in microglia. These data suggest that CB2 inverse agonists can serve as novel class of compounds for treating neuroinflammation in central nervous system diseases.

Student Poster 4

ANTITRYPANOSOMAL ACTIVITY OF NOVEL α, β-UNSATURATED KETONES AND AROYL DERIVATIVES

Karsten Amezcua1, Felipe Rodriguez1, Jonathan Dimmock2, Rosa Maldonado1

1Department of Biological Sciences, University of Texas at El Paso, El Paso, Tx, 79968 2Department of Chemistry University of Saskatoon, Saskatoon, SK S7N 5A2

Chagas disease is an indigenous parasitic disease causing 15,000 annual deaths in South America, Central America and in the south borderline area of the United States. It is estimated that 8-10 million people are currently infected in Latin America with new cases reported in the United States. Trypanosoma cruzi is a protozoan parasite that causes Chagas disease. Only two drugs are available to treat this disease, benznidazole and nifurtimox. They have partial efficacy in the chronic phase of the disease and are highly toxic. It is imperative to find a more effective and less toxic treatment. In this study we evaluated in vitro a drug library consisting of 21 α, β-unsaturated ketones and 15 N-aroyl derivatives for anti-trypanosomal activity and cytotoxicity against mammalian cells. Epimastigote forms of T. cruzi CL Brenner Luc were used to assess the antiparasitic activity of the compounds through a luciferase viability assay. The compounds showed low toxicity to human osteoblast cells (U2-OS). Thirteen of α, β-unsaturated ketones and three N-aroyl compounds showed good anti-trypanosomal activity with an EC50 ranging from 0.016 to 1 uM and a selective index (SI) ranging from 16.5 to 3,125. The compound NC1833 showed the highest SI. Our future directions include a) to determine the compounds activity against amastigotes (intracellular form of the parasite) by High-Content imaging (HCI), b) tested in the murine model of Chagas disease and c) to explore the possible mode of action of the lead(s) compounds.

Student Poster 5

DETERMINING MECHANISM OF THIAZOLE BIOACTIVATION USING EXPERIMENTAL AND COMPUTATIONAL TECHNIQUES

Dustyn Barnette1, Mary Davis1, Matthew Matlock2, S. Joshua Swamidass2, Grover Miller*1

1* Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205 2 Department of Pathology and Immunology, Washington University, St. Louis, MO, 63130

Thiazoles are biologically active aromatic heterocyclic five-membered rings occurring frequently in drug compounds. In most cases, thiazole-containing molecules undergo harmless elimination; however, the structural motif elicits a hepatotoxic response often due to epoxidation of the 4,5 carbon-carbon double bond that ultimately leads to reactive thioamide. The structural diversity of the molecules plays a role in determining whether the molecule undergoes elimination or bioactivation, yet the determinants of those competing possibilities remain unknown. The very different toxic potential between the nonsteroidal anti-inflammatory drugs meloxicam and sudoxicam provide an example of the effect of structure on toxic risk. The presence of a single methyl group on the thiazole of meloxicam, but not sudoxicam, led to meloxicam approval for market while sudoxicam was discontinued due to hepatotoxic outcomes in clinical trials. The metabolic mechanisms differentiating between bioactivation and detoxification for the drugs have not been clearly defined, as the pathways contain multiple, unstudied reaction steps. We hypothesize that the methyl substituent on the thiazole group has no direct impact on the efficiency of the bioactivation pathway, but rather decreases toxic risk through introduction of a competing detoxification pathway. We are employing computational and experimental approaches to test the hypothesis. Although qualitative, our modeling suggested the methyl group does not impact the likelihood for epoxidation of the ring on the path to reactive metabolite formation. As a complement to that work, we are carrying out quantitative kinetic experiments to characterize competing metabolic pathways for meloxicam and sudoxicam. Knowledge of the mechanistic details for these pathways will provide insight for understanding the difference in their toxic outcomes as determined by the substituent. Findings from this study will be transformative in advancing an understanding of what governs thiazole bioactivation, and the knowledge gained could inform drug design of compounds containing the frequently used thiazole scaffold.

Student Poster 6

Assessing variations in SNVs identified using different versions of human genome Pan bohu1

1National Center for Toxicological Research, U.S. Food & Drug Administration, Jefferson, AR 72079, USA

Reference genome selection is a key step in the analysis of next generation sequencing (NGS) data. HG19 and HG38 are the newest two versions of human reference genome in current practices of NGS data analysis. HG19 is older but has comprehensive annotation resource in clinical research while HG39 is newer and contains the most up-to-dated genomic information. Coordinates of the two versions have been analyzed and released by The University of California, Santa Cruz (UCSC). However, concordance in the SNVs identified by using HG19 and HG38 has not been assessed. We conducted comparative analysis on the SNVs identified from the whole genome sequencing (WGS) data of genome-in-a-bottle (GIAB) project using HG19 and HG38. SNVs were first called using 20 different pipelines from the alignments of GIAB data on HG19 and HG38. Two conversion tools, Picard and CrossMap, were then used to convert coordinates of the SNVs between HG19 and HG38. We calculated conversion rates to measure the portion of the coordinates that can be converted between the two versions. We also determined the termed discordant SNVs that were successfully converted but were not be able to identified using another version to assess the concordance in SNVs between the two versions. The alignments on the two versions showed significant differences in the genome coverages, especially for the genomic regions with >450X and <100X reads aligned. We found that more SNVs (average 4.5%) were called from the alignments on the newer HG38 than the alignments on the older HG19. The conversion rates from HG38 to HG19 (average 99%) are higher than the conversion rates from HG19 to HG38 (average 95%). Around 1.5% of the converted SNVs were discordant between HG19 and HG38. The low confidence SNVs defined by GIAB had a higher discordant rate than the high confidence SNVs. The discordant SNVs with bases C and G showed a higher likelihood (52% observed versus 42% expected) compared to those with bases A and T (48% observed versus 58% expected). The discordant SNVs could be caused by the reference genomes or/and the conversion tools. Our findings suggest that cautions should be taken when translating genetic results from different reference genomes.

Student Poster 7

DERIVATIVE OF CIPROFLOXACIN AS A POTENTIAL ANTIBACTERIAL AGENT FOR TREATMENT OF BONE INFECTION.

Shobanabu Bommagani and Peter A. Crooks*

Department of Pharmaceutical Sciences, College of Pharmacy1, Department of Microbiology & Immunology, College of Medicine2, University of Arkansas for Medical Sciences, Little Rock, AR 72205

Osteomyelitis is a serious inflammatory condition of bone that is most often associated with infection by the bacterial pathogen Staphylococcus aureus. Treatment of these infections is extremely challenging owing in part to the increasing prevalence of S. aureus strains resistant to methicillin and other beta-lactam antibiotics. Previous studies have demonstrated that the bone targeting agent BT2-minipeg-2 conjugated to vancomycin and delivered systemically by intravenous (IV) or intraperitoneal (IP) injection has similar antibiotic activity as Vancomycin and accumulates in bone to a greater degree than vancomycin alone, but that this was associated with severe nephrotoxicity. Therefore, there is an urgent need for more effective systemic delivery of antimicrobial agents to bone. We have designed and synthesized several BT2-minipeg-2 conjugates of the quinolone antibiotics such as ciprofloxacin, sparfloxacin and moxifloxacin (BS- 6-21, BS-6-32, BS-6-35, BS-6-39, BS-6-49, BS-6-68, and BS-6-71). These conjugates were initially tested for their antibacterial activity. Most of these conjugates were less potent (less than 50-fold activity) compared to the corresponding parent antibiotic. Interestingly, the BT2-minipeg- 2 ciprofloxacin conjugate, BS-6-68, demonstrated significant antibacterial activity (25% activity of the parent compound). Pilot in vivo studies with the BS-6-68 were carried out to select an appropriate dosing for IP Injection of BS-6-68 and the parent compound ciprofloxacin. IP doses of 10 mg/kg ciprofloxacin or 22.2 mg/kg BT2-minipeg-2 ciprofloxacin (the molar eq. of 10 mg/kg ciprofloxacin) were investigated utilizing female C57BL/6 mice (20-25 g) per experiment. The levels of ciprofloxacin and BT2-minipeg-2 ciprofloxacin in plasma and bone tissues were determined by a new LC-MS/MS method. BS-6-68 and ciprofloxacin were both detected in plasma and bone after IP administration of BS-6-68, indicating that some metabolic cleavage to ciprofloxacin had occurred; ratios (AUC) of BS-6-68:ciprofloxacin were 3.4 and 0.58 in bone and plasma, respectively. After IP administration of ciprofloxacin the drug was detected in both plasma (80%) and bone (20%). The molar ratio of ciprofloxacin in bone after IP administration ciprofloxacin and BS-6-68/ciprofloxacin in bone after IP BS-6-68 administration was 0.8, indicating a 20% increase in molar concentration of BS-6-68/ciprofloxacin. The research was supported by DoD grant W81XWH-15-1-0716

Student Poster 8

RELEASING STUDY OF SIGNALING MOLECULE, HYDROGEN SULFIDE BY 1, 2, 4- THIADIAZOLIDINE-3, 5-DIONE DERIVA

Suresh K. Bowroju1, Narsimha R. Penthala1, Eloisi C. Lopes4, Meenakshisundaram Balasubramaniam3,Karl D. Straub2, Monica L. Guzman4, Peter A. Crooks*1

1Department of Pharmaceutical Sciences, College of Pharmacy, 1Department of Biochemistry & Molecular Biology, Central Arkansas Veterans Healthcare System, 3Department of Geriatrics, College of Medicine University of Arkansas for Medical Sciences, Little Rock, AR-72205 and 4Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065

Developing hydrogen sulfide (H2S) releasing moieties is one of the emerging areas, since H2S is an endogenous modulator that plays significant physio-pathological roles in several biological systems. In our earlier work, we studied the antileukemic activity of TDZD-8 (1) analogs and also reported the unusual rapid cell death kinetics (typically < 2 h) by TDZD analogs. We have now shown in vitro that heterocycle ring opening of TDZD analogs through nucleophilic attack of thiols at the ring sulfur atom results in cleavage of the sulfur-nitrogen bond, leading to formation of an electrophilic disulfide adduct that can react with a second thiol molecule to form an intermediate that releases H2S and generates a terminal disulfide product. We speculate that such a mechanism, if it involves reaction of an endogenous molecule containing a cysteine residue, may explain how these TDZD analogs exert their antileukemic activity at the cellular level. We have now synthesized and identified several novel TDZD analogs whose H2S releasing properties have been evaluated in vitro after exposure to a variety of thiols. These analogs include simple TDZD analogues (2-3), amino-TDZD analogues (4a-4j) and TDZD-disulfide analogs (5a-5d) as H2S- releasing compounds, and have evaluating these analogs against leukemia MV4-11 cells using the MTT assay. TDZD analogs containing an N-2-iodoethyl group and N-2-iodopropyl group (3 and 4f), and a ring opened TDZD analog incorporating a phenethyldisulfide group (5c) exhibited potent antileukemic activity against MV4-11 cells with LD50 values of 1.8 µM, 0.8 µM and 0.75 µM, respectively. Further development of these molecules as clinical candidates to treat leukemia are under investigation.

Student Poster 9

USING STRUCTURE-BASED AND BIOLOGICAL DESCRIPTORS TO ENHANCE THE PREDICTION OF DRUG-INDUCED LIVER INJURY

Cord Carter1,2, Cesar M. Compadre1, Weida Tong2, Shraddha Thakkar2

1Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205 2Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079

Background: Fluoroquinolones are a family of broad spectrum, systemic antimicrobial agents have been therapeutically used to treat respiratory and urinary tract infections. However, several fluoroquinolones have been subsequently withdrawn from the market after spontaneous reports of drug-induced liver injury. Drug-Induced Liver Injury (DILI) produced by drugs that are in the market is a major concern for the patients, regulatory agencies and pharmaceutical industry. DILI is often missed in preclinical stages of drug development as it occurs only in rare cases. Drug- induced liver injury accounts for more than 50% of acute liver failure cases. The development of computational paradigms that could help to predict the DILI is one of the priorities of many regulatory agencies. To provide a rational background to those efforts, we have developed a quantitative structure-activity relationship (QSAR) model that could help identify structural features that could be linked to DILI. Methods: In this study, QSAR was used to generate models and predict the Anti-Toxoplasma inhibitory activity for the 24 published fluoroquinolones (R. Gozalbes et al. Antimicrobial Agents and Chemotherapy Oct 2000, 44 (10) 2771-2776). The fluoroquinolones were built and optimized using the Sybyl program (x2.1 version). Structure-based descriptors were generated by Sybyl software. The correlation between the chemical structures and biological activity was analyzed by using Partial Least Squares (PLS) analysis. Comparative molecular field analysis (CoMFA) was employed to analyze the quantitative structure-activity relationship model of the fluoroquinolones analogues. Results The CoMFA model obtained the partial least-squares (PLS) statistical results, cross- validated correlation coefficient (q2) of 0.763, non-cross-validated correlation coefficient (r2) of 0.929 with standard error of estimate (SEE) of 0.242. Conclusions: These QSAR models that contain in vitro assay data and structural descriptors will help us gain a better understanding on how these drugs can cause drug-induced liver injury.

Student Poster 10

Ribosomal Proteins for Better Resolution in Microbial Taxonomy

Skylar Connor1,2, Visanu Wanchai2, Zulema Udaondo2, David Ussery2

1Joint UALR/UAMS Bioinformatics Program, University of Arkansas at Little Rock, Little Rock, Arkansas, 72204 2Department of Biomedical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205

Background: 16S ribosomal RNA (16S rRNA) is the standard for taxonomic classification of bacteria and archaea. “Next-generation” or “second generation” sequence reads are only a few hundred nt in length, too short to obtain the full-length16S rRNA sequence of about 1500 nt. However, even when full-length 16S rRNA sequences are obtained and used to build microbial trees, the highest taxonomic resolution one can get is species level information. This level of resolution is unable to differentiate multiple genomes within the same species; for example, a pathogenic Escherichia coli O157:H7 and Shigella or a commensal strain of E. coli and a probiotic E. coli strain all cluster as the same species. Furthermore, with the level of information provided by the standard method of 16S rRNA sequencing, it is difficult for one to correctly classify rapidly growing organisms, like Vibrio, which have multiple divergent copies of their 16S rRNA. Classification of these genomes ends up being dependent on which one of the many different 16S sequences are chosen. Results: On average each bacterial genome contains a full complement of about 50 ribosomal protein sequences. The genomes from bacterial type strains are used for comparison of genomes from closely related species; as well as representatives from all of the bacterial orders. We have found that ribosomal protein trees are in agreement with known taxonomy, and further, we are able to see strain level separation. Conclusion: We find that ribosomal proteins can be used to build phylogenetic trees for bacterial taxonomy; using high throughput computing this can be extended to the more than a hundred and eighty thousand genomes currently available in GenBank. We have also found that protein gene order and synteny can be used to classify genomic species.

Student Poster 11

STEM CELLS DIFFERENTIATION INTO NEURONS AND OLIGODENDROCYTES ON MICRON CELLULOSE AND ITS CHEMICAL MO

Soma Shekar Dachavaram 1, Krishna D. Sharma 2, Chetan Pandanaboina 3, Thomas Risch 3, Jennifer Y. Xie 4, and Peter A . Crooks * 1

*Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR-72205. 2 Biological Sciences and Arkansas Biosciences Institute, Arkansas State University, Jonesboro, AR-72401. 3 Neuroscience Laboratory, Arkansas Biosciences Institute (ABI), Arkansas State University, Jonesboro, AR-72401. 4 Department of Basic Sciences, New York Institute of Technology College of Osteopathic Medicine, Jonesboro, AR, USA-72401.

Cellulose is the most abundant biopolymer on earth and a valuable alternative to synthetic polymers due to its renewable source, physical strength, and inherent low toxicity. In this current study, micron cellulose (MC) and TEMPO cellulose Form-I (TCF-I) were utilized as an artificial matrix to differentiate neuronal stem cells (NSCs) into neurons and oligodendrocytes (ODCs). We differentiated E14 rat NSCs into neurons for one week. After a week of differentiation, we determined the percentage of cells positive for the neuronal marker βIII tubulin and the glial marker glial fibrillary acidic protein (GFAP) relative to the total cell count. The highest percentage of NSCs differentiated into neurons was on MC (33%) compared to that on poly-D-lysine (PDL, 24%). GFAP positive cells were 10% on cellulose and 15% on PDL. For ODC differentiation, NSCs propagated for 10 days using combinations of platelet-derived growth factor and basic fibroblast growth factor. Then, the cells were collected and plated on MC and TCF-I differentiated for one week using oligodendrocyte differentiation medium containing triiodothyronine. After seven days of differentiation, immunofluorescence data showed that about 70% of NSCs on these surfaces differentiated into receptor interacting protein positive ODCs. About 30% NSCs differentiated into astrocytes identified by GFAP expression. Interestingly, almost all differentiated cells also expressed nestin protein, suggesting that they were probably not fully differentiated. These results indicate that MC and TCF-I cellulose material surfaces could be advantageous for neural differentiation. (This project is supported by the Center for Advanced Surface Engineering (CASE), under the National Science Foundation (NSF) Grant No. OIA- 1457888 and the Arkansas EPSCoR Program).

Student Oral Presentation and Poster 12

BIOACTIVATION OF HALOGENATED AROMATIC DRUGS AS A PRECURSOR TO DRUG-INDUCED HEPATOTOXICITY

Mary A. Davis1, Tyler Hughes2, Shraddha Thakkar3, S. Joshua Swamidass2, Grover Miller1

1Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States 2Department of Pathology and Immunology, Washington University, St. Louis, MO 63130, United States 3Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, Jefferson, AR, 72132

Halogens are increasingly utilized in drug development, yet their potential impacts on toxic risk through enzymatic bioactivation remain understudied. Chemical reactivity trends indicate halogenated drugs are less likely to undergo bioactivation into reactive metabolites like quinones and thus, pose a decreased toxicity risk. However, the list of halogenated molecules inducing hepatotoxicity continues to grow with the introduction of new molecular entities indicating knowledge of halogenated molecule metabolism is insufficient for assessing toxic risk. We hypothesize that the presence, type, and location of halogens on a drug aromatic ring impacts the chemical step toward reactive oxidative product formation (Vmax) based on electronic effects, while enzyme specificity and affinity (Km) determine the concentration-dependent conditions in which the reaction occurs. We are testing this hypothesis with a novel integration of bioinformatic, computational, and experimental approaches to assess metabolic bioactivation potential of halogenated and nonhalogenated structural relatives. First, we extracted 259 halogenated compounds from the FDA DILIrank database. Computational modeling was performed with our Xenosite deep-learning model to identify quinone bioactivation likelihood. Of these compounds, 13 compounds were selected for further study due to high model predictions and ambiguous participation in DILI. Meclofenamate was the highest predicted ambiguous compound and was supplemented by structurally similar N-aryl acetic acid derivatives with varied degrees of DILI risk. We have developed methodologies to adduct quinone metabolites using dansyl glutathione and have established a sensitive HPLC-UV/Vis method to fluorescently detect these metabolites with isomeric specificity. Future work will ascertain reaction kinetics and identify responsible cytochromes P450 to understand the role of halogens in metabolic clearance and bioactivation contributing to drug-induced liver injury (DILI). These findings will provide critical insights on the impact of halogenated compound bioactivation as a precursor to DILI and thus, provide a foundation for better risk assessment in drug discovery and development. NIGMS-T32- GM106999/ NLM-R01-LM012222

Student Poster 13

UTILIZING FDALABEL TO INVESTIGATE ADVERSE DRUG REACTION PATTERNS IN ANTIDEPRESSANT DRUG LABELING

Nathaniel Hill1,2, Taylor Ingle1, Zhichao Liu1, Leihong Wu1, Junshuang Yang1, Guangxu Zhou1, Mary Yang2, Weida Tong1, and Hong Fang1

1National Center for Toxicological Research, U.S. Food & Drug Administration, Jefferson, AR 72079, USA 2Univeristy of Arkansas at Little Rock, Little Rock, AR 72204, USA

Depression, one of the most common mental illnesses in the U.S., affects millions of Americans. As depression rates increase, so does the use of antidepressants, which can have severe adverse drug reactions (ADRs). ADRs and other important information is summarized in drug product labeling (e.g., including Boxed Warning, Warnings and Precautions, and Adverse Reactions) to help ensure safe and effective use of the drug. The ADR patterns of antidepressants have not been well explored in drug labeling. In this study, we attempt to identify potential ADR patterns utilizing the information in drug labeling to promote public awareness of antidepressants. This study investigated the labeling documents for 28 antidepressant drugs in five Established Pharmacological Classes (EPCs) [e.g., Serotonin and Norepinephrine Reuptake Inhibitor (SNRI), Monoamine Oxidase Inhibitor (MAOI)] using FDALabel. FDALabel is a user- friendly searchable database of over 100,000 labeling documents that can be used to extract ADR terms by combining Medical Dictionary for Regulatory Activities (MedDRA) standard terminologies. All 28 antidepressant drugs had Boxed Warnings indicating increased risk of suicide in teens and young adults. Six unique ADRs (depression, completed suicide, death, insomnia, agitation, seizure) were shared among Boxed Warnings, Warnings and Precautions, Overdosage, and Adverse Reactions sections. Hierarchical cluster analysis (HCA) revealed similarities and differences in ADR patterns among EPCs. For example, SNRI drugs duloxetine and milnacipran contained hepatic ADRs (e.g., jaundice, hepatitis, hepatotoxicity, liver injury), while MAOI drugs phenelzine and tranylcypromine contained cardiac ADRs (e.g., myocardial ischemia, palpitations). Identifying ADR patterns in antidepressant drugs can provide valuable information to assess risks and to promote safe and effective treatments for patients. This study suggests that information queried from FDALabel, combined with MedDRA standard terminologies, can provide useful data for ADR analysis and pattern discovery, supporting drug safety research and potentially improving public awareness of antidepressant drugs.

Student Poster 14

HETEROCYCLIC AROMATIC CARBAMATES OF MELAMPOMAGNOLIDE B AS POTENT, ORALLY BIOAVAILABLE ANALOGS FOR T

Venumadhav Janganati1, Zaineb A. F. Albayati1, Zheng Chen1, Earl J. Morris1, Jessica Ponderc, Philip J. Breen1, Craig T. Jordan2 and Peter A. Crooks1

1Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; 2Division of Hematology, University of Colorado, Aurora, CO 80045, USA; c Department of Toxicology, University of Colorado, Aurora, CO 80045, USA

Melampomagnolide-B (MMB) (1), a sesquiterpene lactone isolated from Magnolia grandiflora has anti-leukemic properties similar to parthenolide (PTL). Also, MMB can be synthesized from PTL utilizing selenium oxide oxidation of the C10 methyl group of PTL. Unlike PTL, the MMB molecule has a C-14 allylic hydroxyl functionality, which allows the synthesis of numerous derivatives of MMB by various chemical transformations and conjugations. Recently we designed and synthesized several conjugates of MMB, which exhibited potent anti-cancer activity against both hematological and solid tumor cell lines. In the present study, we have designed and synthesized imidazole and benzimidazole carbamates of MMB (4a-4e) by reaction of MMB with 1,1′-carbonyl-di-(1,2,4-triazole) to afford MMB- triazole (2), which was reacted with various imidazole and benzimidazole amines in dichloromethane at ambient temperature for 4-16 h. The final compounds were purified by silica gel column chromatography, and their structures were confirmed by NMR and HRMS spectrometric analysis. These compounds were screened for anti-leukemic activity against M9 ENL1 cell line. Most of these compounds showed promising anti-leukemic activity (0.9-3.9 µM) compared to the parent compounds PTL (7.0 µM) and MMB (15.5 µM). Moreover, the comparative plasma PK profiles and oral bioavailabilities of MMB and the imidazole carbamate analog 4a in BALB/c male mice indicated that 4a has improved in vivo exposure after oral administration when compared to an equimolar dose of MMB and had a 1.5-fold longer half-life than MMB. The significantly greater oral bioavailability of 4a when compared to that of MMB, coupled with the 16-fold greater antileukemic potency of 4a compared to MMB, predict a potential therapeutic advantage of 4a over an equimolar dose of MMB. This research was supported by NIH grant CA158275 and by an Arkansas Research Alliance (ARA) Scholar award.

Student Poster 15

CATALYST-FREE, C-3 FUNCTIONALIZATION OF IMIDAZO[1,2-A]PYRIDINES TO EXPLORE NEW CHEMICAL SCOPE

Anupreet Kharbanda, Naresh Gunaganti, Naga Rajiv Lakkaniga, Lingtian Zhang, Rose Cooper, Hong-yu Li* and Brendan Frett *

Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, 72205, USA

Multicomponent reactions (MCRs) are robust tools for the generation of diverse, chemical libraries with complex form and function, which can play a crucial role in drug discovery and development. By utilizing MCR chemistry, we developed an economical, catalyst-free, and eco-friendly protocol to synthesise C-3 substituted arylomethylation derivatives of imidazo[1,2-a]pyridines through a three component, decarboxylation reaction involving imidazo[1,2-a]pyridine, glyoxalic acid, and boronic acid; which were further tested for their antiproliferative activities in the oncogenic cell lines.

Student Poster and oral 16

INSIGHTS INTO THE DFG-FLIP AND MECHANISM OF ACTIVATION OF AURORA KINASE B BY METADYNAMICS

Naga Rajiv Lakkaniga1, Meenakshisundaram Balasubramaniam2, Brendan Frett1 and Hong-yu Li1

1Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205 2Department of Geriatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205

Aurora Kinase B (AKB), a Ser/Thr kinase that plays a crucial role in mitosis, is over-expressed in several cancers. Clinical inhibitors targeting AKB are thought to bind the active, DFG-in form of the kinase. It would be beneficial, however, to understand if AKB is susceptible to Type II kinase inhibitors that bind to the DFG-out, inactive conformation, since Type II inhibitors achieve higher kinome selectivity. Unfortunately, the DFG-out conformation of AKB has not been crystallized, which makes design of Type II inhibitors exceedingly difficult. An alternate approach is to simulate the DFG-out conformation from available DFG-in conformations using atomistic molecular dynamics (MD) simulation. In this work, we explored a Metadynamics (MTD) approach to simulate the DFG-out conformation of AKB and examined structural changes during the DFG- flip. Interestingly, the MTD approach also identified unique transition states, which are crystallized in a close homolog of AKB. Knowledge about these conformations is essential for structure-guided design of next-generation AKB inhibitors. This work emphasizes the usefulness of MTD simulations in predicting macromolecular conformational changes accurately with reduced computational efforts.

Student Poster 17

Development of safer benzodiazepines using comparative 3D QSAR and Drug Induced Liver Injury severity and toxicity (DILIst) annotations

Ting Li1,2, Carter Cord3, Cesar M. Compadre3, Weida Tong1, Shraddha Thakkar1

1Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USA 2Bioinformatics, Joint program of University of Arkansas at Little Rock and University of Arkansas for Medical Sciences, Little Rock, AR, USA 3Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences

Liver Injury is one of the most common cause of drug attrition or withdraw from the market. To understand overall distribution of the Drug Induced liver injury (DILI) on approved drugs worldwide, we have developed the comprehensive list containing severity and toxicity (DILIst) . Benzothiazines (BZs) were found to be most frequent occurring chemical subgroup in DILIst. Additionally, bz’s are among the most commonly prescribed medications that demonstrates anxiolytic, sedative, hypnotic, and anticonvulsant activity. BZs-related morbidity and mortality has risen dramatically from 0.6 per 100 000 adults in 1999 to 4.4 per 100 000 in 2016. One of the causes for DILI is either prolonged use or overdose. It is hard to detect the DILI risk of BZs as they do not cause significant serum enzyme elevation. DILI is mainly due to reactive metabolite formation. Understanding the structural basis for the DILI effects and contrasting them with structural requirements for their pharmacological effects would helpful to develop safer benzodiazepines. For this study, we have developed a comparative molecular field analysis (CoMFA) model of the benzothiazines that has ability to inhibit the GABAA receptor effectively and contrasted model with a DILIst annotations to understand the pharmacophore for effective and safer BZ’s. We conducted a CoMFA study of a set of 57 benzodiazepines analogues [Haefely, W. Adv. Drug Res. 14 (1985): 165-322.]. Structures were built using the X-ray crystallography from Cambridge of diazepam using Sybyl_X 2.1. For the CoMFA study steric and electrostatic interactions were calculated using a sp3 carbon atom as steric probe and a +1 charge as electrostatic probe with Tripos force field, with a grid spacing of 2.0 A and 30 kcal/mol. CoMFA of log(1/IC50) in benzodiazepine binding site (BDZ-bs) of the GABAA receptor produced cross-validated q2 value of 0.511 with eight components and non-cross-validated r2 of 0.927. The estimated F value was 76.689 and standard error 0.212. The relative contributions of steric and electrostatic fields were 0.372 and 0.628, respectively. Eight of 57 benzodiazepines had a DILI annotation from the DILIst. Four of them presented no DILI risk. As the figure displayed, the no DILI risk of BZs had moderate to high bioactivity. It is promising to find an approach to develop a new benzodiazepine that has high bioactivity but with no DILI risk.

Student Poster 18

PARTHENIN FROM PARTHENIUM HYSTEROPHERUS, ABLATES ACUTE MYELOGENOUS LEUKEMIA (AML).

David E. Mery1,2,3, Rachel Yang1,2, Paola E. Ordóñez3, Eloy Rodriguez1, Cesar M. Compadre3, and Monica L. Guzman2

1Dept. of Plant Biology, Cornell University, Ithaca, NY 14850, 2Dept. of Hematology/Oncology, Weill Cornell, New York, NY 10065-4896, and 3Dept. of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205

Background: Leukemia stem and progenitor cells are central to leukemia relapse by maintaining and initiating the leukemic cell population. The sesquiterpene lactone (SL) parthenolide (PTL) has raised interest as a potential anti-leukemic compound because its ability to target leukemia stem cells. Unfortunately, PTL’s poor water solubility and relatively low potency limits it’s in vivo effectiveness. In our continued effort to identify SLs with a better pharmaceutical profile, we have uncovered parthenin (PRT), a SL from Parthenium hysterophorus L. Results: PRT was tested in comparison with PTL against a battery comprised of 12 leukemia cell lines, 4 primary leukemia cell samples, and 3 normal PBMC samples. Compared to PTL, PRT kills AML at lower doses (Mean LD50: 6.81 μM vs. 11.56 μM Cell Lines, and 6.80 μM vs 7.91μM Primary Cells), depletes less free thiols and induces less ROS, inhibits NF-κB transcriptional targets better, causes less activation of Nrf2 transcriptional targets, and decreases active NF-κB and HMOX-1 protein levels better. Mechanistically, it is believed that SLs induce apoptosis through inhibition of NF-κB which is upregulated in leukemia cells. Molecular modeling analysis suggests that both PRT and PTL can bind very well to NF-κB because they have a large lipophilic surface formed by C-8, C-9, C-13 and C- 14 that seem to interact with a complementary lipophilic surface in NF-κB. Tetraneurin-E (TET), a SL that is structurally similar to PRT but has a smaller lipophilic contact surface, was tested against the same battery of cells. Interestingly, TET showed no activity against the leukemia cell lines or the leukemia primary cells that have elevated NF-κB levels but showed toxicity against the normal cell lines that have normal NF-κB levels. Conclusions: These results support the hypothesis that the SLS’s mechanism involves interaction with NF-κB and stress the importance of the presence of an extended lipophilic surface for their activity.

Student Poster 19

BRAIN TUMOR DETECTION USING DEEP LEARNING NEURAL NETWORKS

Xiaoxu Na1, Li Ma1, Mariofanna Milanova2, Mary Yang1

1Department of Information Science, University of Arkansas at Little Rock, Little Rock, AR, 72204 2Department of Computer Science, University of Arkansas at Little Rock, Little Rock, AR, 72204

Background: Brain tumor identification using magnetic resonance images (MRI) is widely applied to the tumor diagnosis and treatment, based on the type, location, size of the tumor and other affects. While the segmentation, detection, and extraction of the infected tumor area from MRI are not only a primary concern, but also time taking task performed by radiologist or clinical experts, and their experience may highly influence the accuracy of the result. With the development of deep leaning, as part of a broader family of machine learning methods based on artificial neural networks, it paves the way to improve the processing of the medical images automatically and may support early stage detection of the brain tumor.

Method: We obtained the multimodal brain tumor image segmentation (BRATS) 2015 public raw data from TCGA. The preprocessing procedure of the MRI files included reorientation, de-noising, bias-correcting, skull stripping and co-registration. Based on the truth class labels of 274 cases that the radiologists made the in the challenge BRATS 2015 dataset, we trained our basic convolutional neural network (CNN) and an attention convolutional layer integrated CNN with the 193 subjects. The classification performance was evaluated using 54 subjects. The basic network includes 7 layers that apply 3*3*3 convolutions and 1 layer of 1*1*1 convolution with the PyTorch on the backbone; whereas the attention layer adopts parallel dilated convolutional filters and an attention model to capture both local and global context.

Result: The dice coefficient (DICE) is the most used metric for validating medical volume segmentations. We found the basic network and the attention layer integrated network performed similarly with DICE 73% on the enhancing volume. The attention layer integrated network performed better on the core volume with DICE 73%, and 88% on the whole volume, respectively.

Conclusion: We have demonstrated the preprocessing of the raw MRI files and further implemented a basic CNN and an attention convolutional layer integrated into the basic CNN to challenge the task of brain tumor segmentation in MRI and achieve promising performance. In future, an attention mechanism will be introduced to other layers so that in each layer the output is computed by fusing from outputs of the previous parallel dilated convolutions. We expect to achieve 5-10% increase of accuracy using the proposed model.

Student Poster 20

THE WMN1 ENHANCER REGION IS REQUIRED FOR EXPRESSION OF HUMAN PLP1

Pankaj Patyal, Hamdan Hamdan, Neriman Kockara, and Patricia Wight

Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205, USA

The myelin proteolipid protein gene (PLP1) encodes the most abundant protein present in myelin from the central nervous system (CNS). Its expression must be tightly controlled as evidenced by mutations that alter PLP1 dosage; both overexpression (elevated PLP1 copy number) and lack thereof (PLP1 deletion) result in X-linked genetic disorders in man. However, not much is known about the mechanisms that govern expression of the human gene. To address this, transgenic mice were generated which utilize human PLP1 (hPLP1) sequences [proximal 6.2 kb of 5ʹ-flanking DNA to the first 38 bp of exon 2] to drive expression of a lacZ reporter cassette. LoxP sites were incorporated around a 1.5-kb section of hPLP1 intron 1 since it contains sequence orthologous to the wmN1 region from mouse which, previously, was shown to augment expression of a minimally-promoted transgene coincident with the active myelination period of CNS development. Frt sites were also incorporated in hPLP1 intron 1 in order to remove most of the (8,579 bp) intron. Eight transgenic lines were generated with the parental, 6.2hPLP(+)Z/FL, transgene. All lines expressed the transgene appropriately in brain as evidenced by staining with X-gal in white matter regions and olfactory bulb. Immunostaining against cell-type-specific markers revealed that the 6.2hPLP(+)Z/FL transgene is expressed in oligodendrocytes and oligodendrocyte precursor cells (OPCs), as well as in olfactory ensheathing cells (OECs) and neurons. Removal of the ‘wmN1’ region from 6.2hPLP(+)Z/FL with a ubiquitously expressed Cre- driver caused a dramatic reduction in β-gal activity, throughout development, in the resulting 6.2hPLPΔwmN1 subline. These results demonstrate for the first time that the wmN1 enhancer region: (i) is functional in hPLP1; (ii) works in collaboration with its native promoter – not just a basal heterologous promoter; (iii) is required for high levels of hPLP1 gene activity; (iv) has a broader effect, both spatially and temporally, than originally projected with mouse Plp1 (mPlp1).

Student Poster 21

N-BENZYL AZAINDOLE QUINUCLIDINONES AS NOVEL CANNABINOID LIGANDS

Narsimha R.Penthala,1 Amal M. Shoeib,2 Soma Shekar Dachavaram,1 Paul L. Prather,2 Peter A. Crooks1* 1*Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA 2Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA

Previously, we have reported a novel class of cannabinoid receptor ligands possessing an indole nucleus as a key structural element, along with a quinuclidinone moiety (IQD’s). The IQD ligands bind to both CB1 and CB2 cannabinoid receptors with high affinity in the nanomolar range. The azaindole nucleus is found to be another structural element which has been reported to play a key role in the affinity and activity of synthetic cannabinoids. In the present study a series of N-alkyl/N- benzyl 7-azaindolequinuclidinone (AIQD) analogs (1a-1f, 2a-2b) have been synthesized and evaluated for their affinity toward CB1 and CB2 receptors and are identified as a novel class of cannabinoid receptor ligands. AIQD analogs are more drug like with improved pharmacokinetic properties compared to previously reported IQD analogs. Systematic structure activity relationship studies indicated that AIQD analogs are CB1/CB2 dual cannabinoid receptors ligands exhibiting good affinity at CB receptors, although they have generally lower affinity when compared to IQD’s but are more selective towards CB2. Initial binding screens showed that AIQD analogs 1b, 1d, 1f and 2b (1 mM) produced more that 50% displacement of the CB1/CB2 non-selective agonist CP- 55,940 (0.1 nM), which predicts that these compounds likely exhibit sub-micromolar affinity for both CB1 and CB2 receptors. Furthermore, Ki values determined from full competition binding curves showed that analogs 1a and 1b exhibit high affinity (110 and 115 nM) and selectivity (26.3 and 6.1-fold) for CB2 relative to CB1, respectively. Collectively, these initial studies suggest that further structure optimization of AIQD analogs may lead to the development of clinical useful AIQD cannabinoid agents.

Acknowledgements: We are grateful to the NIA/ NIH- P01AG012411-17A1 (PAC)

Student Poster 22

DOMINO UGI-N3/C-H ACTIVATION SEQUENCE: EXPEDIENT SYNTHESIS OF ANNULATED TETRAZOLYL PYRIDO-IMIDAZO QU

Debasmita Saha1, Anupreet Kharbanda1, Nkeseobong Essien1, Lingtian Zhang1, Rose Cooper1, Debasish Basak2,b Samantha Kendrick2,Brendan Frett*1 and Hong-yu Li*1

1Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences; Little Rock, Arkansas, 72205 2Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences; Little Rock, Arkansas

A one-pot, efficient synthesis of a series of tetracyclic tetrazolyl pyrido-imidazo quinolines was designed via a sequential Ugi-N3 reaction followed by a novel AgOAc-mediated Pd catalyzed intramolecular C-H activation of the Ugi-Azide adducts. The reaction has a broad tolerance and substrate scope. Title compounds were screened against a cancer cell panel, and 6af exhibited selective, antiproliferative activity against the MCF-7 cell line. This methodology can reach new chemical-space and generate hit compounds to expedite pharmaceutical development.

Student Poster 23

THE ROLE OF OMA1 IN COLD STORAGE-INDUCED RENAL INJURY

Julia Tobacyk, Nirmala Parajuli, John Crow and Lee Ann MacMillan-Crow

Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 The numbers of patients on transplant waiting lists continues to grow primarily due to a shortage of donor kidneys. Kidneys from deceased donors are subjected to cold storage (CS) preservation while waiting for tissue matching and transplantation. Sadly, 34% of donor kidneys have to be discarded due in part to CS-induced injury. Numerous studies have demonstrated that CS induces renal and mitochondrial dysfunction. Our recent study revealed that mitochondrial fusion and fission pathways are impaired in rat kidneys exposed to CS and transplantation (PMID: 28977005). This study identified two key proteins involved in the fusion machinery that were significantly impaired in kidneys exposed to CS followed by transplantation: Optic Atrophy Protein (OPA1) which is cleaved by a stressed-induced mitochondrial protease, OMA1. We hypothesize that mitochondrial fusion is compromised due to abnormal activation of OMA1 during CS and transplantation which leads to excessive mitochondrial damage. The goal of this study is to establish mechanistic groundwork of OMA1 in CS-induced renal injury using two in vitro cell models designed to modulate OMA1 expression: 1) normal rat kidney (NRK) proximal tubular cells (+/- OMA1 siRNA) exposed to cold storage + rewarming (CS+RW) to mimic reperfusion in our rat renal transplant model and 2) wildtype (WT) mouse embryonic fibroblasts cells (MEF) and OMA1 knockout (KO) MEF cells exposed to CS+RW. Using the OMA1 activity assay, a novel and fluorescent-based assay developed in our lab for measuring OMA1-dependent OPA1 processing, we show increased OMA1 activity during CS or CS+RW in both NRK and MEF cells lines (n=3). Knockdown of OMA1 restored the balance between short and long form of OPA1 processing during CS suggesting a return to normal mitochondrial fusion (n=3). In addition, OMA1 knockdown resulted in a 67% increase in ATP-dependent cell viability compared to scramble siRNA treated NRK cells exposed to CS (n=3). In summary, these data suggest that activation of OMA1 appears to be a detrimental event leading to mitochondrial damage during renal CS. Future studies will use our novel OMA1 activity assay and ongoing collaboration with Cayman Chemicals to identify/design pharmacological OMA1 inhibitors that could be added to kidneys during CS to alleviate mitochondrial and renal injury. Most importantly, therapeutic use of OMA1 inhibitors could increase the numbers of donor kidneys that are transplanted as well as function of the transplanted kidney. This research is supported in part by NIH T32GM106999, PhRMA Foundation, and a Sturgis Pilot study.

Student Poster 24

ACTIVITY OF COLCHICINE DERIVATIVES TOWARDS PRIMARY ALL AND BREAST CANCER CELLS

Alicja Urbaniak1, Fariba Jousheghany2, Youzhong Yuan2, Sergio Pina-Oviedo2, Magdalena Delgado1, Urszula Majcher3, Greta Klejborowska3, Adam Huczyński3, Behjatolah Monzavi-Karbassi2, Thomas Kieber-Emmons2, and Timothy C. Chambers1

1Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205 2Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205 3Department of Bioorganic Chemistry, Adam Mickiewicz University, Poznań, 61-614

Colchicine (COL) shows strong anti-cancer activity related to its ability to bind to tubulin causing microtubule depolymerization, mitotic arrest, and cell death. However, due to the toxicity of COL towards normal cells, identification of new therapeutics based on COL structure is warranted. In order to increase potency and reduce toxicity against normal cells, a library of novel COL analogs, namely N-carbamates of N-deacetyl-4-(bromo/chloro/iodo)thiocolchicine, has been synthesized. COL and several of the derivatives arrested MCF-7 cells in mitosis, and caused microtubule depolymerization. Compounds were then tested against two types of primary cancer cells; adult acute lymphoblastic leukemia (ALL) cells, and human breast cancer (BC) cells derived from newly excised human tumor tissue. These represent more clinically relevant drug screening models compared to established cell lines. Four novel colchicine derivatives showed higher activity towards primary ALL cells (IC50 = 1.1 ± 0.5 to 6.4 ± 1.4 nM) and nine were more potent towards primary BC cells (IC50 = 2.3 ± 0.0 to 10.3 ± 4.6 nM) compared to COL (IC50 = 8.6 ± 0.2 nM and 11.7 ± 3.1 nM, respectively) in cell viability assays. COL and two of the most active derivatives were also shown to be effective in killing BC cells when tested ex vivo using fresh human breast tumor explants derived from residual invasive ductal carcinoma and invasive mucinous carcinoma. The present findings indicate that the COL derivatives described here constitute promising lead compounds for targeting acute lymphoblastic leukemia and different subtypes of breast cancer. The present study was funded by a grant (to TCC) from the Arkansas Breast Cancer Research Program. Financial support by grant (to AH, UM, GK) of the Polish National Science Centre (NCN) – No. 2016/21/B/ST5/00111 is gratefully acknowledged.

Student Poster 25

SYNTHESIS AND ANTIMICROBIAL STUDIES OF POTENT 4-[1-(4- CARBOXYPHENYL)-4-FORMYL-PYRAZOL-3-YL]BENZOIC ACID DERIVES

Jedidiah Whitt1, MdMahbubKabir Khan1, Anthony Sumlin1, David Gilmore2, and Mohammad A. Alam*1

1*Department of Chemistry and Physics, College of Science and Mathematics, Arkansas State University, Jonesboro, Arkansas, 72467 2Department of Biological Sciences, College of Science and Mathematics, Arkansas State University, Jonesboro, Arkansas, 72467

The Centers for Disease Control and Prevention recently stated that the number of antibiotic- resistant infections has increased to more than two million per year, and these infections are responsible for 23,000 deaths in the United States annually. The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) are responsible for 80% of nosocomial infections. Traditional antibiotics have failed to treat many of these infections, as new bacterial machinery have evolved to combat the functional mechanisms of standard drugs, thus there is a great demand for new antimicrobial compounds. However, due to the complex nature of bacterial cell walls and outer membranes, drug design is limited to molecules that can easily accumulate within the bacterial cell. The pyrazole scaffold has been observed in a variety of drugs that are effective analgesic, anti-inflammatory, antidepressant, anti-mycobacterial, anti-tumor, antiviral, as well as antimicrobial agents. Based on our previous reports, we have designed many novel pyrazole-derived compounds containing a carboxylic acid functional group to test against ESKAPE pathogens. These novel structures were synthesized in our lab, and contained a reactive aldehyde group for subsequent attachment of hydrazine substituents. The compounds were screened for activity against our bacterial strains and MIC values were recorded. Some of the most potent compounds are being tested against A. baumannii in Galleria mellonella in vivo model. In this presentation, synthesis of aniline analogues of hydrazones will also be discussed. This work is supported by INBRE Research Development Grant.

Student Poster 26

PATIENT TIMEFRAME SIGNALING USING THE FDA ADVERSE EVENT REPORTING SYSTEM (FAERS) DATABASE

Matthew Windsor

University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205

The FDA Adverse Event Reporting System (FAERS) public dashboard offers many options to query potential safety concerns. A key limitation of the public dashboard is the ability to position the adverse event (AE) reporting on a patient level timeframe (timeframe agnostic). The inclusion of the time interval between drug administration and the start of the AE and/or the time interval between last dose and start of reaction or event allows a more nuanced approach to FAERS analysis by which confounders such as concomitant medication can be analyzed. Methods The E2BM data elements for B.2.i.7.1 (time interval between drug administration) and B.2.i.7.2 (time interval between last dose and start of reaction or event ) were indexed to the FDA specific designated medical events list (DMA) n79 for 26 SSRI medications within FAERS. Results were ordered to mean time to event (MTE) and the mean time between dose and event (MTDE).

Student Poster 27

DRUG LABELING IDENTIFICATION THROUGH SCENE-TEXT RECOGNITION AND SEMANTIC SIMILARITY ANALYSIS

Xiangwen Liu1, Xiaowei Xu2, Weida Tong1, Leihong Wu1, Joshua Xu1

1 FDA/National Center for Toxicological Research, 3900 NCTR Rd., Jefferson, AR 72079, USA 2 University of Arkansas at Little Rock, 2801 S. University Ave., Little Rock, AR 72204, USA

[Aim/Background] The FDA’s presence at the International Mail Facilities (IMF) provides a front- line defense against illegal, illicit, unapproved, counterfeit and potentially dangerous drugs from entering the United States. However, due to extremely time-consuming process for investigation (including preparing, screening, testing, identification, decision making) and limited personnel of investigators, only a small fraction of the mail packages has been reviewed. Our system aims to accelerate investigation by learning patterns from the historical reference dataset and providing candidates for the investigator to make the final decision.

[Methods] We take advantages of rich text information on drug package and drug label to build an AI-based deep learning model to learn patterns of historical data and recognize suspicious drugs from that pattern. A deep learning model Connectionist Text Proposal Network (CTPN) is trained and utilized for text detection as our first step of text mining. Then cropped images are recognized through Tesseract OCR Engine for text similarity analysis. Finally, we applied combined Levenshtein Distance Similarity algorithms to present top candidates through similarity scores.

[Result] FDALabel and DailyMed are utilized for Text detection and recognition. We trained (CTPN) on ICDAR 2015 dataset. Based on our trained model, the recognition result on our Daily Med images has up to 89.7% of word accuracy comparing to ground truth. In addition, the Tesseract OCR engine recognize 90.4% of cropped texts from CTPN in multi-languages. Finally, A public dataset is downloaded from Google Images using randomly selected 13 drug names. Among Top 5 candidates provided by combined Levenshtein Distance Similarity algorithms, 80% of the candidates from reference dataset either have the same brand or same function with the test drug. From the promising result, we can conclude that our approach ultimately extract texts from images and contribute on accelerating investigation process.

Student Poster 28

A STATISTICAL METHOD TO IMPROVE BIOMARKER DETECTION IN UNCERTAIN QPCR DATA

Wei Vivian Zhuang1, Luísa Camacho2, Camila S Silva2, and Huixiao Hong1

1Division of Bioinformatics and Biostatistics, NCTR, FDA, Jefferson, AR 72079 2Division of Biochemical Toxicology, NCTR, FDA, Jefferson, AR 72079

Recent studies have revealed that circulating microRNAs are promising biomarkers for non-invasive detection of toxicity and diseases such as cancer. As a medium-throughput technique, qPCR (Quantitative Real-time Polymerase Chain Reaction) is often used to measure the expression levels of genes and microRNAs. Besides complete data, investigators have observed inevitably incomplete qPCR data due to lowly expressed or completely unexpressed transcripts. Investigators often intervene with incomplete qPCR data in an intrinsic way, such as setting incomplete observations equal to the maximum number of qPCR cycles (MC), applying the complete- observation method by deleting the incomplete observations from analysis (CO), or choosing not to analyze targets with incomplete observations (CNA). The three methods tend to cause biased inference, decrease research reproducibility across replicate experiments, and thus be ineffective and inefficient in helping investigators learn from incomplete qPCR data. To overcome the shortcomings, we propose a nonparametric cycle-to-threshold method (CTOT). CTOT incorporates qPCR-specific features and the time-to-event statistical methodology, and is built around extracting information from all subjects, censored or not. We used simulations and a dataset of rat serum microRNAs to compare the performance of CTOT, MC, CO, and CNA. Our simulations show that CTOT may improve the power of detecting differentially expressed biomarkers without generating excess type I errors. In the application, CTOT detected potentially differential expression that would be otherwise overlooked. CTOT helps leverage qPCR technology, increases the power to detect novel biomarkers, and improves research reproducibility. This study may help improve the MIQE guidelines (minimum information for publication of qPCR experiments). The source funding: This work was supported by Division of Bioinformatics and Biostatistics and Division of Biochemical Toxicology, NCTR, U.S. FDA. Its contents are solely the responsibility of the authors and do not reflect any position of the U.S. FDA.

Student Oral 29

ACTIVATION OF METABOLIC SPACE OF Cystobacter ferrugineus BY INTERCEPTING QUORUM SENSING MOLECULES

Shukria Akbar1, D. Cole Stevens*1

1* Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, University of Mississippi, Oxford, MS 38677

Most of world’s biodiversity is composed of bacteria that are a major source of currently available antimicrobials. The discovery of structurally novel antimicrobials as well as understanding of their role in their natural environment require not only the exploration of underexploited bacterial genera but also the investigation of their interaction with other bacteria and the signaling molecules present in a specific niche. Myxobacteria are underexposed soil predatory bacteria that have a high potential to produce natural products with great chemical diversity. Microbes in a functional community communicate with each other through signaling molecules such as quorum sensing molecules (QSMs). The existence of QSMs modifying elements within genomes of myxobacteria that do not produce the cognate QSMs provide support for a necessary chemical communication between myxobacteria and their potential prey bacteria in the soil. Using enzymology not yet associated with biosynthetic gene clusters (BGCs), we have observed perception and transformation of exogenous quorum signal such as 2-heptyl-4(1H)-quinolone (HHQ) by a myxobacterium, Cystobacter ferrugineus. LC-MS/MS analyzed data of the extracts obtained by bacterial cultivation with HHQ was used to create molecular networks by using Global Natural Products Social Molecular Networking (GNPS) for the visual presentation of the effects of HHQ on the bacterial secondary metabolome. Our results have shown that HHQ have induced the production of cryptic specialized small molecules in C. ferrugineus. Understanding the chemical basis of myxobacterial manipulation of quorum signals from potential prey bacteria will not only bridge the gap in our knowledge of bacterial chemical ecology in the soil, but also will provide us an opportunity to activate dormant BGCs associated with potentially active small molecules.

Student Poster 30 9 SYNTHESIS AND ANTIMICROBIAL STUDIES OF POTENT 4-[1-(4- CARBOXYPHENYL)-4-FORMYL-PYRAZOL-3-YL]BENZOIC ACID DERIVES

Jedidiah Whitt1, MdMahbubKabir Khan1, Anthony Sumlin1, David Gilmore2, and Mohammad A. Alam*1

Oral Presentation 31

ANTI-METASTATIC CAPACITIES OF MELATONIN RECEPTOR AGONISTS ON DIFFERENT BREAST CANCER CELL LINES

Alev Tascioglu Aliyev1,2, Kimberly J. Krager2, Nukhet Aykin-Burns2, Hande Gurer Orhan1

1 Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ege University, Izmir, Turkey, 35040 2 Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA,72205

Clinical studies have shown patients diagnosed with triple negative breast cancers (TNBC) or luminal type breast cancers that have a higher expression of melatonin receptors exhibited increased survival rates (1, 2). In vitro studies also revealed that antiproliferative actions of melatonin on various subtypes of human breast cancer cell lines (3). Melatonin’s oncostatic mode of action is believed to be through melatonin receptor dependent pathways, unfortunately it has poor bioavailability and short half-life. The melatonin receptor has a higher affinity for the melatonin agonists, agomelatine and ramelteon, than melatonin as well as better bioavailability. Since the agonists are currently approved for major depressive disorder and insomnia respectively, repurposing of agomelatine and ramelteon against breast cancer therapy and/or prevention would be a cost effective approach. Therefore in the present study, agomelatine and ramelteon were evaluated for their antiproliferative and antimetastatic actions on TNBC cell line (MDA-MB-231) and ER (+) breast cancer cell line (MCF-7) by conducting colony formation, MTT and transwell assays. Agomelatine and ramelteon decreased the colony formation on MCF-7 cells, yet neither agonists displayed short-term cytotoxicity. The compounds inhibited the migration rate in both cell lines however; only agomelatine suppressed the migration and invasion of MDA-MB-231 cell line in transwell assays. In conclusion, agomelatine demonstrated promising results against two different subtypes of breast cancer but the mechanism underlying these effects have yet to be elucidated. This study was supported by Ege University Research Fund grant 18-ECZ-008, NIH NIGHMS P20GM109005 and UAMS FY19 Chancellor Award.

1. Oprea-Ilies, Gabriela, et al. Breast cancer research and treatment 137.3 (2013): 677-687. 2. Jablonska, Karolina, et al. Journal of pineal research 54.3 (2013): 334-345. 3. Hill, Steven M., et al. Endocrine-related cancer 22.3 (2015): R183-R204.

Oral Presentation 32

SPECIES IDENTIFICATION OF FOOD CONTAMINATING BEETLES THROUGH ELYTRAL PATTERN ANALYSIS

Tanmay Bera1, Lauren Fuller2, Leihong Wu1, Hongjian Ding3, Howard Semey3, Zhichao Liu2, Amy Barnes3, Himansu Vyas3, Weida Tong2, Joshua Xu2*

1- Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR. 2- Department of Biology, University of Arkansas, Little Rock, AR. 3- Food Chemistry Laboratory 1, Arkansas Laboratory, Office of Regulatory Affairs, US Food and Drug Administration, Jefferson, AR.

Insect pests, such as pantry beetles, are one of the major causes of food contamination and wastage. Currently, manual micro-analysis is used to first find the beetle remains and subsequently identify them using anatomical features. This makes the whole process less efficient to handle with increasing number of food samples. To address this challenge, we proposed to use a combination of image acquisition and automated machine learning methods to identify the species of food contaminating beetles. Previously, our studies have shown good potential in such species identification through elytral pattern recognition. Our studies have also indicated that optimizing imaging technique that yields high quality elytral images may further improve the accuracy of this technique. Herein, we explored various optical settings (such as optical filters, lighting conditions, magnifications etc.) to obtain a standard imaging condition that can consistently produce good quality, high resolution (HR) images of beetle elytra across various species of pantry beetles. Imaging set-up optimization resulted in acquiring distinct microscopic images of elytra for 6 different species of pantry beetles that were most challenging in identification. The images were detailed enough to allow distinguishing one species from another, even for beetles from the same genus. We subsequently created an HR image database for 50 different species of pantry beetles which would account for almost all insect-based food contaminations. Work is currently underway to develop an efficient pattern recognition algorithm that can yield high species level identification accuracy for this extensive array of beetle species. In summary, our work demonstrates that a combination of image acquisition and image processing technique is the key in achieving better accuracy for identifying the species of food contaminating beetles. *Corresponding Author: Joshua Xu ([email protected])

Oral Presentation 33

IDENTIFICATION OF NOVEL DRUGS FOR TREATEMENT OF NEURODEGENERATIVE DISEASES BY QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP

Samuel Kakraba,1,2 Narsimha R. Penthala,3 Peter A. Crooks,3 Cesar M. Compadre,3 Robert J. Shmookler Reis,2,4 and Srinivas Ayyadevara2,4

1Bioinformatics program, University of Arkansas for Medical Sciences and Univ. of Arkansas at Little Rock, Little Rock, AR 72205 2Department of Geriatrics and 3Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205 4Central Arkansas Veterans Healthcare System, Little Rock, AR 72205

Background: Cytotoxic protein aggregation is characteristic of age-associated neurological disorders such as Alzheimer's disease. Our goal is to identify compounds that are effective at reducing cytotoxic protein aggregation as potential drug for neurodegenerative diseases. We use SH-SY5Y-APPSw neuroblastoma cells as a model of amyloidopathy to identify lead candidates. The lead candidates are further characterized using a Caenorhabditis elegans CL4176 model that accrue aggregates and develop progressive paralysis with age, and a C. elegans AM141 that is used to model Huntington disease. The results of the bioassays are analyzed using quantitative structure-activity relationship (QSAR) techniques to identify the structural factors responsible for the activity and enable us to design strategies to optimize the activity and properties of the lead compounds. Results: Several compounds tested reduced age-associated protein aggregation relative to untreated controls, in both SH-SY5Y-APPSw human neuroblastoma cells and C. elegans strains AM141 and CL4176. Our data are consistent with protection, by these anti-inflammatory compounds, against protein aggregation and associated traits. Conclusion: Our results provide a basis for considering anti-inflammatory drugs and related compounds as novel therapeutic agents to prevent or treat protein-aggregation disorders. Further studies are needed to understand the mechanisms by which these effects arise, to predict optimal features for active molecules, and thus to develop bioactive pharmacological interventions. Acknowledgements: This project was funded by the U.S. Department of Veteran Affairs Merit Review Grant (BX001655, RJ Shmookler Reis, PI), the U.S. National Institute of Health (National Institute on Aging) Program Project Grant (AG012411-17A1, WST Griffin, PI), and by a grant from NIGMS (P20 GM103429) at NIH.

Oral Presentation 34

THE ROLE OF NON-CODING RNA AND mRNA INTERATIONS IN REGULATION OF DRUG METABOLIZING ENZYMES AND HEPATOTOXICITY

Dongying Li1, Leihong Wu1, Dianke Yu2, Bridgett Knox1, Si Chen1, Lei Guo1, Weida Tong1, and Baitang Ning*1

1National Center for Toxicological Research, US FDA, Jefferson, AR, 72079 2School of Public Health, Qingdao University, Qingdao, China

Long noncoding RNAs (lncRNAs) play an important role in many physiological and pathological pathways by regulating gene expression through diverse mechanisms, including serving as a microRNA sponge. Altered expression of lncRNAs have been observed in response to drug exposure and associated with drug toxicity. However, little is known about the role of lncRNAs in drug metabolism and drug induced liver toxicity (DILI). We used acetaminophen-treated human hepatic cells as a hepatoxicity model and identified 121 differentially expressed lncRNAs potentially associated with acetaminophen toxicity via RNA sequencing. We then analyzed expression correlation between identified lncRNAs and key drug metabolizing enzyme (DME) mRNAs and found that LINC844 was positively correlated with CYP3A4, CYP2E1 and SULT2A1 on the expression level. Our results from gain- and loss-of-function assays suggested that LINC844 mediates SULT2A1 expression in human hepatoma HepG2 cells. Additionally, we demonstrated that miR-486-5p and miR-495-3p suppressed SULT2A1 expression by binding to the 3'-UTR of SULT2A1 mRNA. Sequence alignment and binding affinity analysis showed multiple miR-486-5p binding sites on LINC844. Inhibition of miR-486-5p, but not miR-495-3p, upregulated both SULT2A1 and LINC844. We demonstrated that LINC844 regulates SULT2A1 expression by titrating miR-486-5p away from SULT2A1 mRNA and inhibiting microRNA- mediated gene silencing. This study illustrates a complex network of ncRNA and mRNA interactions and provides potential novel biomarkers and therapeutic targets in mediating drug efficacy and toxicity.

Oral Presentation 35

CONTRIBUTIONS TOWARDS UNDERSTANDING THE DIFFERENCES IN BIOLOGICAL ACTIVITY AMONG THE VARIOUS VITAMIN-E’S TOCOLS.

Ujwani Nukala1,2, Awantika Singh1,2, Shraddha Thakkar3, Nukhet Aykin-Burns1,5, Rajeshkumar Manian, Philip J. Breen1,5 Mahmoud Kiaei4, Rupak Pathak1, Weida Tong3, and Cesar M. Compadre1,5

1Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, 2Joint Bioinformatics Graduate Program, University of Arkansas at Little Rock, Little Rock, AR 72204, 3Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, 4Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, 5Tocol Pharmaceuticals, LLC, Little Rock, AR 77205, USA

The risk of radiation exposure has been increasing with increased use of ionizing radiation for nuclear power plants or nuclear weapons, both of which can result in accidental radiological emergencies. Vitamin E’s anti-oxidant potential may be a major factor for their radioprotective activity. The vitamin E family consists of eight different vitamers, including four tocopherols (α, β, γ and δ) and four tocotrienols (α, β, γ and δ). These compounds have relatively minor structural differences but have shown substantial differences in their pharmacokinetic and pharmacological profile. In order to gain an understating for such differences we have studied tocol’s differential behavior with regard to their cell uptake levels, gene expression and pharmacokinetics, using experimental and computational techniques. Our results suggest a paradigm in which the observed differences can be explained by a multifactorial function:

Tocol therapeutic efficacy = Fn (intrinsic activity, elimination rate, cell-uptake)

Oral Presentation 36

ROBUST LIQUID CHROMATOGRAPHY TANDEM MASS SPECTROMETRY METHOD TO SIMULTANEOUSLY QUANTIFY PHYTOSTEROLS AND TOCOPHEROLS ENTRAPPED IN LIPOSOMAL FORMULATION.

Asmita Poudel1, George Gachumi1, Zafer Dallal Bashi1, Ildiko Badea1 and Anas El-Aneed1

1College of Pharmacy and Nutrition, University of Saskatchewan

Purpose: Phytosterols and tocopherols extracted from canola oil waste stream can be a potential component of nutraceuticals due to their cholesterol lowering abilities and antioxidant properties, respectively. We have developed lipid-based formulations, liposomes, to entrap these lipophilic and thermosensitive bioactives for their effective utilization in the food industry as a nutraceuticals. However, prior to nutraceutical development, analytical strategies should be developed to quantify these bioactives, entrapped within the liposomal bilayer. Thus, we developed and validated a liquid chromatography tandem mass spectrometry method (LC- MS/MS) to simultaneously quantify phytosterols and tocopherols entrapped in liposomes. Method: LC-MS/MS method (I) was developed and validated as per International Council for Harmonization (ICH) guideline. Chromatographic separation of the analytes was carried out on poroshell C18 column protected by a guard column of the same packing material. For fast analysis, a similar method (II) was developed but with the use of a guard column alone. For both methods, a simple isocratic elution consisting of acetonitrile: methanol (99:1 v/v) with 0.1% acetic acid was utilized. The detection and quantification were performed using an API 6500 QTRAP® quadruple-linear ion trap (QqQ-LIT) mass spectrometer equipped with an atmospheric pressure chemical ionization (APCI) source. The method is validated for selectivity, accuracy, precision, reproducibility, sensitivity, matrix effects, dilution integrity, stability were assessed. Results: Method I showed a total run time of 7 minutes whereas method II was merely a 2- minute run. Both methods showed adequate linearity (R2 = 0.999 for phytosterols and R2 = 0.998 for tocopherols). Validation parameters such as selectivity, accuracy, precision, repeatability, sensitivity, matrix effects, dilution integrity and stability were within the acceptable guidelines for method I. Further, method I was applied for the analysis of liposomal formulation and the entrapment efficiency achieved was greater than 90%. Method II is currently being validated. Conclusion: In sum, we successfully developed LC-MS/MS methods with analysis run times of 7 minutes and 2 minutes for method I and II, respectively. The validated method was applied to simultaneously quantify liposomal phytosterols and tocopherol. In the future, validation of method II will be conducted and subsequently adapted for regular analysis due to the short run time. The analytical method will be cost effective as solvent amount and instrument usage costs are reduced.

Oral Presentation 37

ENGINEERING 89ZR-LABELED AMINO ACID FUNCTIONALIZED DIAMOND NANOPARTICLES FOR GENE DELIVERY: METHOD DEVELOPMENT, OPTIMIZATION, STABILITY STUDY AND BIODISTRIBUTION STUDIES

Raj Rai, Saniya Alwani, Ed Krol, Humphrey Fonge and Ildiko Badea

College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK Canada.

Purpose: To map biodistribution of lysine and lysyl-histidine functionalized NDs (collectively ‘fND’) employed as gene carriers. Biodistribution and pharmacokinetic studies will elucidate their fate at organ level. Method: lysine and lysine histidine fNDs were synthesized via covalent conjugation using a 3- carbon chain linker. 1HNMR was used to confirm synthesis of amino acid conjugates at all steps. Extensive method development was carried out to deduce the best synthetic approach for designing radio labeled fNDs. Briefly, after synthesizing fNDs, a chelating agent ‘deferoxamine’ was conjugated to allow labeling with a radio nuclei Zirconium 89 (89Zr). Thermograms of fNDs from previous analyses were used to quantify the percentage of DFO conjugation on the surface. DFO was conjugated at 8%, 6%, 3% and 1% and characterized to maintain size and positive surface without compromising optimum radiolabeling efficiency. Pharmacokinetic and biodistribution studies of 89Zr labeled fNDs were performed in CD-1 mice using ex vivo gamma counter and microPET/CT imaging. Results: Among all conjugation ratios of 1-8%, 3% DFO conjugation to fNDs maintained the optimal size of under 200nm and positive surface charge of +19.4±4.1 mV. The conjugates formed diamoplexes (DFO conjugated fNDs/siRNA complexes) at biocompatible mass ratios. Radiolabeling method was developed and optimized with respect time and temperature achieving more than 90% efficiency. The radiolabeling efficiency remained stable in phosphate buffer saline and mouse blood serum for over 96 hours (97±2%). Biodistribution assays revealed high accumulation of fNDs in liver after 6 hours (6.11±4.06) and 72 hours (2.32±2.09) followed by spleen (0.17±2.71 at 6 hours and 1.66±1.31 at 72 hours). PET images further confirmed the finding of biodistribution assays. Conclusion: This study establishes an understanding of in vivo behavior of fNDs for future design, optimization and application of these novel carriers for targeted gene therapy.

Oral Presentation 38

DEVELOPMENT AND VALIDATION OF ESTROGEN RECEPTOR BETA BINDING PREDICTION MODEL USING LARGE SETS OF CHEMICALS

Sugunadevi Sakkiah, Huixiao Hong*

Division of Bioinformatics and Biostatistics, NCTR/FDA, Jefferson, AR (*Correspondence at [email protected]; 870-543-7296)

Endocrine system plays a vital role in the human body. Chemicals that bind with estrogen receptor (ER) could mimic natural hormone and thus might disrupt or improve the endocrine system. ER has two major isoforms, ER and ER . Concentrations of these two types of ER are different in tissues. Chemicals that selectively bind to one type of ER could selectively act on ER and are called selective estrogen receptor modulators (SERMs). Therefore, binding activity of chemicals to ER and ER is needed for identification of SERMs. We previously developed in silico model for prediction of ER binding. In this study, we developed QSAR model for ER binding prediction using the pattern recognition algorithm Decision Forest and a large training data set that contains 2500 compounds. The ER binding activity of the chemicals in the training data set was obtained from EADB (Estrogenic Activity Database) that was developed at FDA. To estimate performance of prediction model constructed from the training data set, 1000 iterations of 5-fold cross validation were conducted. The model was validated using a large external sets extracted from ToxCast Project. Our results revealed that the models performance well in both internal and external validations. Informative chemical features for ERβ binding were identified through analysis of the frequency data of chemical descriptors used in the models using the 5-fold cross validations. Based on our knowledge, this is the first in silico model for predicting ERβ binders based on large sets of experiment data. Coupling with our previously developed ER binding prediction model, the ER binding prediction model developed in this study could be expected to facilitated identification SERMs and help risk assessment of environment chemicals through ER mediated endocrine activity.

Oral Presentation 39

DEVELOP A DATABASE OF HERBAL/ DIETARY SUPPLEMENTS (HDS) HEPATOTOXICITY FOR SUPPORTING THE FDA’S NEW EFFORTS TO STRENGTHEN REGULATION OF HDS PRODUCTS

Minjun Chen

Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas 72079, USA

The growing use of herbal dietary supplements (HDS) in the U.S. provides compelling evidence for risk of herbal induced liver injury (HILI). We retrieved information on about 300 unique HDS products from MedlinePlus of the U.S. National Library of Medicine, and the herbal monograph of the European Medicines Agency. Based on published case reports for assigning the hepatotoxic potential of HDS, we found evidence of hepatotoxicity reported for 67, that is one in five, of these HDS products. The database revealed clear gender preponderance with women at higher risk for HILI. Culprit hepatotoxic HDS were mostly used for weight control, followed by pain and inflammation, mental stress and mood disorders. Commonly discussed mechanistic events associated with HILI are reactive metabolites and oxidative stress, mitochondrial injury as well as inhibition of transporters. HDS-drug interactions causing both synergistic and antagonizing effects of drugs were also reported for certain HDS. The database contains information for nearly 300 commonly used HDS products to provide a single-entry point for a better comprehension of their impact on public health.

Oral Presentation 40

DRUG REPOSITIONING FOR NOONAN AND LEOPARD SYNDROME BY INTEGRATING TRANSCRIPTOMICS AND STRUCTURE-BASED APPROACH

Liyuan Zhu1, Ruili Huang2, Jinghua Zhao2, Menghang Xia2, Brian Delavan1,3, Mike Mikailov4, Weida Tong1*, Zhichao Liu1*

1 National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079 2 National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA 3 Joint Bioinformatics Graduate Program, University of Arkansas at Little Rock and University of Arkansas for Medical Sciences, Little Rock, AR 72204, USA 4 Office of Science and Engineering Labs, Center for Devices and Radiological Health, US Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993, USA * To whom correspondence should be addressed: [email protected] or [email protected]

Noonan and LEOPARD syndrome (NS and LS) belong to a group of related disorders called RASopathies characterized by abnormalities of multiple organ and systems. There are no approved drugs for these two rare diseases, highlighting their unmet medical needs. In this study, we proposed a hybrid computational drug repositioning framework by integrating transcriptomic and structure-based approach for exploring treatment options for NS and LS. Specifically, disease signatures were extracted from transcriptomic profiles tested under human iPSC of NS and LS patients, and further reversely correlated to the drug transcriptomic signatures from CMap and L1000 projects. Then, we docked top-ranked compounds from transcriptomic approach to mutated and wild 3D structures of PTPN11 by a proposed adjusted Induced Fit Docking (IFD) protocol. Final, we prioritized repositioning candidates for NS and LS by a consensus ranking strategy. We found the transcriptomic approaches could discriminate the two diseases at molecular level using network analysis and phenotypic anchoring. Furthermore, the proposed adjust IFD protocol could effectively reflect binding specificity of repositioning candidates to mutated 3D structures. Moreover, the binding pattern of repositioning candidates and amino acids were analyzed. Importantly, a list of repositioning candidates including 61 for NS and 43 for LS were obtained and further verified with both literature reports and on-going clinical trial studies. We also experimentally verified the one repositioning candidate of LS (i.e., dasatinib) on the external mouse and human iPSC for its low-dose perturbation ability on the cardiomyopathy. Altogether, the proposed hybrid drug repositioning approach is promising and may be applied to other diseases as well.

Keywords: transcriptomic profiles; molecular docking; iPSC; drug repositioning; rare diseases

Oral Presentation 41

FDALABEL DATABASE AT AMAZON CLOUD WITH RICH DRUG LABELING INFORMATION TO ADVANCE THE APPLICATION OF PRECISION MEDICINE Hong Fang

National Center for Toxicological Research, U.S. FDA, Jefferson, Arkansas 72079

FDA’s Structured Product Labeling (SPL) archive, which stores drug labeling documents submitted by manufacturers, contains labeling information including product indications, dosing recommendations, contraindications, drug interactions, warnings and precautions, adverse reactions, and information for patients to help ensure the safe and effective use of the product. The continual increase in the number of labeling documents and large amount of data contained in these documents necessitates an advanced bioinformatics tool with powerful drug data management and search capabilities. We have developed the FDALabel database as a web-based application, containing over 100,000 drug labeling documents from FDA’s SPL archive. FDALabel allows the public to perform customizable (any combination of sections, document types, market categories, and other information), full-text searches of product labeling on a relational oracle database. A new version of FDALabel (v2.3), available at Amazon Cloud: https://nctr-crs.fda.gov/fdalabel/, was developed to search human prescription drug and biological product labeling and human over-the-counter (OTC) drug labeling. To demonstrate the FDALabel database’s utility, we have selected study cases including a pharmacogenomics study for Precision Medicine and an ADR (Adverse Drug Reaction) study that applied Medical Dictionary for Regulatory Activities (MedDRA) standard terminologies. We identified 224 drugs with 289 drug- biomarker pairs across different therapeutic areas such as oncology (103), psychiatry (33), and infectious diseases (32). We also found severe ADRs were prevalent in MedDRA System Organ Classes such as Nervous system disorders, Psychiatric disorders, and Cardiac disorders. The FDALabel database search tool offers the public, researchers and regulatory reviewers an efficient and user-friendly means of accessing and searching the large amount of information contained in drug labeling. An Amazon Cloud version of FDALabel (v 2.3) supports and promote translational medicine and regulatory science by employing advanced computer technologies to deliver end- users a reliable, effective, and efficient search tool.

MCBIOS AND MAQC SOCIETY JOINT ANNUAL MEETING

April 6-8 2020 17th ANNUAL MEETING OF MCBIOS Precision Public Health – A 2020 VISION For more information contact - Weida Tong , PhD, President, MCBIOS - [email protected]

April 8-10 2020 th 4 ANNUAL MEETING OF MAQC Society Reproducibility – A 2020 VISION For more information contact - Wendell Jones , PhD, President, MAQC Society - [email protected]

APRIL 8TH, 2020 - JOINT WORKSHOP, POSTER, AND RECEPTION

LOCATION SAS INSTITUTE, CARY, NORTH CAROLINA