Kohen Curriculum Vitae

Total Page:16

File Type:pdf, Size:1020Kb

Kohen Curriculum Vitae Curriculum Vitae Amnon Kohen Department of Chemistry Tel: (319) 335-0234 University of Iowa FAX: (319) 335-1270 Iowa City, IA 52242 [email protected] EDUCATION AND PROFESSIONAL HISTORY Education D.Sc., Chemistry 1989-1994 Technion – Israel Institute of Technology, Haifa, Israel Advisor: Professor T. Baasov Topic: Mechanistic Studies of the Enzyme KDO8P Synthase B.Sc., Chemistry (with Honors) 1986-1989 Hebrew University, Jerusalem, Israel Positions Professor 2010-Present Department of Chemistry, University of Iowa, Iowa City, IA and Molecular and Cellular Biology Program, and MSTP faculty member Associate Professor 2005-2010 Department of Chemistry, University of Iowa, Iowa City, IA and Molecular and Cellular Biology Program Assistant Professor 1999-2005 Department of Chemistry, University of Iowa, Iowa City, IA Postgraduate Researcher 1997-1999 With Professor Judith Klinman Department of Chemistry, University of California, Berkeley Topic: Hydrogen Tunneling in Biology: Alcohol Dehydrogenases Postgraduate Fellow 1995-1997 With Professor Judith Klinman Department of Chemistry, University of California, Berkeley Topic: Hydrogen Tunneling in Biology: Glucose Oxidase Visiting Scholar Fall 1994 With Professor Karen S. Anderson Department of Pharmacology, Yale Medical School, New Haven, CT Kohen, A. Affiliations American Society for Biochemistry and Molecular Biology (ASBMB, 2013 - present) Center for Biocatalysis and Bioprocessing (CBB) University of Iowa (2000-Present) The Interdisciplinary Graduate Program in Molecular Biology, University of Iowa (2003- Present) American Association for the Advancement of Science (AAAS, 2011-present) American Chemical Society (1995-Present) Divisions: Organic Chemistry, Physical Chemistry, Biochemistry Sigma Xi (1997-Present) Protein Society (1996-1998) Honors and Awards • Career Development Award (University of Iowa- 2015-2016) • Graduate College Outstanding Faculty Mentor Award (2015). • The Lady Davis Visiting Professorship (The Lady Davis Fellowship Trust, Israel – 2009) • Faculty Scholars Award (University of Iowa- 2007-2010) • Career Development Award (University of Iowa- 2006-2007) • NSF Faculty Early Career Development (CAREER) Award (2002-2007) • Wolf Foundation Award for excellence in doctoral studies (1992) • Miriam and Aaron Gutwirth Award for excellence in graduate studies (1991) • Amos-De-Shalit Scholarship for distinguished undergraduate students (1987) • Hebrew University Dean’s List (1987-1989) SCHOLARSHIP Publications All the publication below are in a peer reviewed journals and books. (* = Corresponding author, senior author, major contribution) Publications resulting from work performed at Iowa: 1. Morris, H., Singh, P., Kohen, A.,* Tivanski, A.,* “Probing Single Molecule Enzyme-Drug Interaction with Molecular Recognition Force Spectroscopy:., Submitted to J. Am. Chem. Soc. April 7, 2015. 2. Francis, K., Kohen, A.,* “Dihydrofolate Reductase as a Model for Enzyme Catalysis”, Current Biotech., 4, 1-10, 2015. (Invited review). 3. Singh, P., Francis, K., Kohen, A.,* “Network of remote and local protein dynamics in dihydrofolate reductase catalysis”, ACS Cat., 5, 3067–3073, 2015. 4. Guo, Q., Pagano, P., Li, Y., Kohen, A., Cheatum, C.M.,* “Line Shape Analysis of Two-dimensional Infrared Spectra”, J. Chem. Phys., 142, 212427, 2015. PMCID: PMC4409623 5. Ghosh, A.K., Islam, Z., Krueger, J.D., Abeysinghe, D.T., Kohen, A.,* “The General Base in the Thymidylate Synthase Catalyzed Proton Abstraction”, Phys. Chem. Chem. Phys. Accepted for publications, Just accepted articles on line, April 15, 2015. 2 Kohen, A. 6. Świderek, K., Kohen, A., Moliner, V.,* “Influence of Active Site Conformations on the Hydride Transfer step of the Thymidylate Synthase Reaction Mechanism”, Phys. Chem. Chem. Phys. Accepted for publication April 1, 2015. 7. Abeysinghe, T., Kohen, A.,* “Role of Long-Range Protein Dynamics in Different Thymidylate Synthase Catalyzed Reactions”, Int. J. Mol. Sci., 16, 7304-7319, 2015. Special Issue on Protein and Protein- Lingand Interactions. 8. Nilaweera, T., Saeed, M. and Kohen, A.,* “Targeting the de novo Biosynthesis of Thymidylate for the Development of PET Probe for Pancreatic Cancer Imaging”, Biochemistry, 54, 1287–1293, 2015. Chosen to be highlighted on the journal’s home page: http://pubs.acs.org/journals/bichaw/index.html. 9. Singh, P., Abeysinghe, T., Kohen, A.,* “Linking Protein Motion to Enzyme Catalysis”, Molecules, 20, 1192-1209, 2015. (Invited review) 10. Doron, D., Stojković, V., Gakhar, L., Kohen, A., Major, D.,* “Free Energy Simulations of Active-Site Mutants of Dihydrofolate Reductase”, J. Phys. Chem. B., 2015, 119, 906–916. 11. Kohen, A.,* “Role of Dynamics in Enzyme Catalysis: Substantial vs. Semantic Controversies”, Acc. Chem. Res., 2015, 48, 466–473. (Special Issue on “Enzymes Dynamics and Catalysis”) 12. Singh, P., Morris, H., Tivanski, A.V., Kohen, A.,* “Determination of concentration and activity of immobilized enzymes”, Submitted to Anal., Biochem., Accepted for publication Feb. 12, 2015. http://dx.doi.org/10.1016/j.ab.2015.02.014 13. Singh, P., Morris, H., Tivanski, A.V., Kohen, A.,* “A calibration curve for immobilized dihydrofolate reductase activity assay”, Data in Brief, 2015, 4, 19-21. 14. Mishanina, T., Kohen, A.,* “Synthesis and application of isotopically labeled flavin nucleotides”, Submitted to J. Labeled Comp. Radiopharma., Accepted for publication with minor revision Dec. 26, 2014. 15. Liu, C.T.,‡ Francis, K.,‡ Layfield , J., Huang, X., Hammes-Schiffer, S., Kohen, A.,* Benkovic, S.J.,* “The Escherichia coli Dihydrofolate Reductase Catalyzed Proton and Hydride Transfers: Order and the Roles of Asp27 and Tyr100”, Proc. Nat., Acad. Sci. USA, 2014. 111, 18231–18236. 16. Klinman, J.P.,* Kohen, A,* “Evolutionary Aspects of Enzyme Dynamics”, J. Biol. Chem., 2014. 289, 30205-30212. 17. Mishanina, T., Corcoran, J.M., Kohen, A.,* “Substrate Activation in Flavin-Dependent Thymidylate Synthase”, J. Am. Chem. Soc., 2014, 136, 10597–10600. 18. Roston, D., Kohen, A., Doron, D., Major, D.T.,* “Simulations of Remote Mutants of Dihydrofolate Reductase Reveal the Nature of a Network of Residues Coupled to Hydride Transfer”, J. Comp. Chem., 2014, 35, 1411-1417. 19. Islam, Z., Strutzenberg, S.T., Gurevic, I., and Kohen, A.*, “Concerted versus Step-Wise Mechanism in Thymidylate Synthase”, J. Am. Chem. Soc. 2014,136, 9850–9853. 20. Wang, Z., Singh, P., Czekster, C., Kohen, A.,* Schramm, V.L.,* “Protein Mass-modulated Effects in the Catalytic Mechanism of Dihydrofolate Reductase: Beyond Promoting Vibrations”, J. Am. Chem. Soc., 2014, 136, 8333-8341. 21. Doron, D., Kohen, A., Nam, K., Major, D.T.,* “How Accurate are Transition States from Simulations of Enzymatic Reactions?” J. Chem. Theory Comput., 2014, 10, 1863-1871. 3 Kohen, A. 22. Francis, K., Kohen, A.,* “Protein Motions and the Activation of the C-H Bond Catalyzed by Dihydrofolate Reductase”, Curr. Opinion Chem. Biol., 2014, 21, 19–24. (Invited Review). 23. Singh, P., Sen, A., Francis, K., Kohen, A.,* “Extension and limits of the network of coupled motions correlated to hydride transfer in dihydrofolate reductase”, J. Am. Chem. Soc., 2014, 136, 2575–2582. 24. Roston, D., Kohen, A.,* “Stereospecific Multiple Isotopic Labeling of Benzyl Alcohol”, J. Labeled Comp. Radiopharma., 2014, 57, 75-77. 25. Roston, D., Islam, Z., Kohen, A., “Kinetic Isotope Effects as a Probe of Hydrogen Transfers to and from Common Enzymatic Cofactors”, Archives Biochem. Biophys, 2014, 544, 96-104. 26. Francis, K., Kohen, A., “Standards for the Reporting of Kinetic Isotope Effects in Enzymology”, Perspectives in Science, 2014, 1, 110–120. A STRENDA and Beilstein book, Eds. Cornish-Bowden, A., and Cattenr, C., Pub. Elsevir. (Invited Chapter). 27. Francis, K., Stojković, V., Kohen, A.,* “Preservation of Protein Dynamics in Enzyme Evolution“, J. Biol. Chem., 2013, 288, 35961-35968. 28. Roston, D., Kohen, A.,* “A Critical Test of the “Tunneling and Coupled Motion” Concept in Enzymatic Alcohol Oxidation”, J. Am. Chem. Soc., 2013, 135, 13624–13627. 29. Islam, Z, Roston, D., Kohen, A., “Isotope effects as probes for H-tunneling and enzyme dynamics”, Special Issue on "Isotope Effects" in Molecules, Ed. Hansen, P.E., 2013, 18, 5543-5567. (Invited Review). 30. Wang, Z., Sapienza, P.J., Abeysinghe, T., Luzum, C., Lee, A.L., Finer-Moore, J.S., Stroud, R.M., and Kohen, A.,* “Mg2+ binds to the surface of thymidylate synthase and affects hydride transfer at the interior active site”, J. Am. Chem. Soc., 2013. 135, 7583-7592. 31. Wang., Z., Ferrer, S., Moliner, V.,* Kohen, A.,* “QM/MM calculations suggest a unique mechanism for the proton abstraction catalyzed by thymidylate synthase”, Biochemistry, 2013, 52, 2348-2358. 32. Kohen, A, “Positron emission tomograpgy tracer“, US 2013/0034496 A1, Patent application published Feb. 7, 2013. 33. Cheatum, C.M.,* Kohen, A,* “Relationship of Femtoseconds Dynamics to the Catalyzed Hydrogen Transfer” Topics in Current Chemistry, Special issue on “Macromolecular Dynamics in Biological Catalysis”, Eds, Hammes-Schiffer, S. & Klinman, J.P., Pub: Elsevier, (Invited Review). Published on-line March 28, 2013. 34. Kohen, A.*, Klinman, J.P.*, “Hydrogen Tunneling Links Protein Dynamics to Enzyme Catalysis”, Ann. Rev. Biochem., 2013, 82, 471–496. (Invited Review). 35. Wang, Z., Abeysinghe, T., Finer-Moore, J.S., Stroud, R.M., Kohen, A.*, “A Remote Mutation Affects the Hydride Transfer by Disrupting Concerted Protein Motions in Thymidylate Synthase”, J. Am. Chem. Soc., 2012, 134, 17722-17730. 36. Vardi-Kilshtain, A.,
Recommended publications
  • Molecular Cloning, Expression and Enzymatic Assay of Pteridine Reductase 1 from Iranian Lizard Leishmania
    Iranian Biomedical Journal 14 (3): 97-102 (July 2010) Molecular Cloning, Expression and Enzymatic Assay of Pteridine Reductase 1 from Iranian Lizard Leishmania Bahram Kazemi*1,2, Farideh Tohidi3,4, Mojgan Bandehpour1 and Fatemeh Yarian1 1Cellular and Molecular Biology Research Center and 2Dept. of Parasitology and Mycology, Shahid Beheshti University, Tehran; 3Dept. of Parasitology and Mycology, Gorgan University of Medical Sciences, Gorgan; 4Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran Received 17 April 2010; revised 17 July 2010; accepted 24 July 2010 ABSTRACT Background: Currently, there are no effective vaccines against leishmaniasis, and treatment using pentavalent antimonial drugs is occasionally effective and often toxic for patients. The PTR1 enzyme, which causes antifolate drug resistance in Leishmania parasites encoded by gene pteridine reductase 1 (ptr1). Since Leishmania lacks pteridine and folate metabolism, it cannot synthesize the pteridine moiety from guanine triphosphate. Therefore, it must produce pteridine using PTR1, an essential part of the salvage pathway that reduces oxidized pteridines. Thus, PTR1 is a good drug-target candidate for anti-Leishmania chemotherapy. The aim of this study was the cloning, expression, and enzymatic assay of the ptr1 gene from Iranian lizard Leishmania as a model for further studies on Leishmania. Methods: Promastigote DNA was extracted from the Iranian lizard Leishmania, and the ptr1 gene was amplified using specific primers. The PCR product was cloned, transformed into Escherichia coli strain JM109, and expressed. The recombinant protein (PTR1 enzyme) was then purified and assayed. Results: ptr1 gene was successfully amplified and cloned into expression vector. Recombinant protein (PTR1 enzyme) was purified using affinity chromatography and confirmed by Western-blot and dot blot using anti-Leishmania major PTR1 antibody and anti-T7 tag monoclonal antibody, respectively.
    [Show full text]
  • Design, Synthesis and Biological Evaluation of Novel Inhibitors of Trypanosoma Brucei Pteridine Reductase 1 Daniel Spinks, Han B
    MED DOI: 10.1002/cmdc.201000450 Design, Synthesis and Biological Evaluation of Novel Inhibitors of Trypanosoma brucei Pteridine Reductase 1 Daniel Spinks, Han B. Ong, Chidochangu P. Mpamhanga, Emma J. Shanks, David A. Robinson, Iain T. Collie, Kevin D. Read, Julie A. Frearson, Paul G. Wyatt, Ruth Brenk, Alan H. Fairlamb, and Ian H. Gilbert*[a] Genetic studies indicate that the enzyme pteridine reductase 1 chemistry and structure-based approaches, we were able to (PTR1) is essential for the survival of the protozoan parasite Try- derive compounds with potent activity against T. brucei PTR1 app m panosoma brucei. Herein, we describe the development and (K i = 7n ), which had high selectivity over both human and optimisation of a novel series of PTR1 inhibitors, based on ben- T. brucei dihydrofolate reductase. Unfortunately, these com- zo[d]imidazol-2-amine derivatives. Data are reported on 33 pounds displayed weak activity against the parasites. Kinetic compounds. This series was initially discovered by a virtual studies and analysis indicate that the main reason for the lack screening campaign (J. Med. Chem., 2009, 52, 4454). The inhibi- of cell potency is due to the compounds having insufficient tors adopted an alternative binding mode to those of the nat- potency against the enzyme, which can be seen from the low m m ural ligands, biopterin and dihydrobiopterin, and classical in- Km to Ki ratio (Km =25 n and Ki = 2.3 n , respectively). hibitors, such as methotrexate. Using both rational medicinal Introduction Human African trypanosomiasis (HAT) is a serious health prob- lem in sub-Saharan Africa, with an estimated 50 000 new infec- tions each year, and over 60 million people in 36 countries are at risk of infection.[1] HAT is a progressive and ultimately fatal disease.
    [Show full text]
  • Curriculum Vitae Natalie G. Ahn
    Natalie G. Ahn Curriculum Vitae Natalie G. Ahn ADDRESS: Department of Biochemistry Jennie Smoly Caruthers Biotechnology Building 3415 Colorado Avenue, 596 UCB University of Colorado at Boulder Boulder, CO 80309-0596 Phone: (303) 492-4799 (Phone) Email: [email protected] I. ACADEMICS EDUCATION Postdoctoral Fellow, 1988-1990, Department of Pharmacology, Univ. of Washington, Seattle Research advisor: Edwin G. Krebs Postdoctoral Fellow, 1985-1987, Department of Medicine, Univ of Washington, Seattle Research advisor: Christoph de Haën Ph.D.,1985, Department of Chemistry University of California, Berkeley Thesis advisor: Judith P. Klinman 1979-1981 Teaching Assistant, undergraduate chemistry, Dept. of Chemistry 1981-1985 Research Assistant, Dept. of Chemistry B.S., 1979, Department of Chemistry, University of Washington, Seattle Undergraduate senior thesis advisor: Lyle H. Jensen, Department of Biological Structure Undergraduate research advisor: David C. Teller, Department of Biochemistry APPOINTMENTS 2018-present Distinguished Professor, University of Colorado 2003-present Associate Director, BioFrontiers Institute, Univ. Colorado, Boulder 1994-2014 Investigator, Howard Hughes Medical Institute (1994-2002 Assistant Investigator; 2003-2004 Associate Investigator; 2005-2014 Investigator) 1993-present Member, UCHSC Cancer Center, Univ. Colorado Health Sciences Center, Denver 1992-2018 Professor, Department of Chemistry and Biochemistry, Univ. Colorado, Boulder (1992-1998 Assistant Professor; 1998-2003 Associate Professor; 2003-present Professor) 1990-1992 Research Assistant Professor, Department of Biochemistry, Univ. Washington, Seattle 3 Natalie G. Ahn II. HONORS 2018 Distinguished Professor, University of Colorado 2018 Member, National Academy of Sciences 2018 Member, American Academy of Arts and Sciences 2016-2018 President, American Society of Biochemistry and Molecular Biology 2012 Professor of Distinction, College of Arts & Sciences, U.
    [Show full text]
  • Minnesota Academy of Science Newsletter
    Fall 2014 Vol. 6, No. 3 Minnesota Academy of Science Newsletter Your Support Can Make a Difference By Celia Waldock, Executive Director Innovation is widely recognized as a driver of economic growth with STEM professions the basis for a successful, globally competitive and innovative US and Minnesota economy. By 2018, Minnesota will need to fill 188,000 STEM and STEM-related jobs.1 During the next decade, overall U.S. demand for scientists and engineers is expected to increase at four times the rate for all other occupations.1 And STEM education is the essential element. Everyone needs to have the fundamental STEM skills that form the basis for lifelong In this Issue learning – inquiry, observation, analysis, synthesis and reinvention. Yet in 2011, 8th-graders in 11 other countries achieved higher The importance of STEM Ed ...1 averages in mathematics scores than in the US, performing at or Donate Stock .................3 above the Advanced international mathematics benchmark. At the same time, 8th-graders in 12 other countries achieved higher Message from the President ..4 averages in science scores than in the US, performing at or above Science Salon.................5 the Advanced international science benchmarks.2 Fracking Wastewater .........8 Notably, only one in five STEM college students felt that their K–12 The World of 3M Innovation . 9 education prepared them extremely well for their college courses Smith Hall Centennial........10 in STEM.3 And the number of U.S. companies reporting difficulty in Archiving the Journal ........12 filling positions because of a lack of skills grew from 14 percent in 4 Winchell Advisor Perspective 13 2010 to almost 40 percent by 2013.
    [Show full text]
  • Dihydropteridine Reductase
    John M. Whiteley et uf. : Dihydropteridine reductase Pteridines Vol. 4, 1993, pp. 159-173 Review Dihydropteridine Reductase John M. Whiteley§, Kottayil I. Varughesej:, Nguyen H. Xuong#, David A. Matthews, t and Charles E. Grimshawf §The Scripps Research Institute, La Jolla, CA 92037, USA., #University of California at San Diego, La Jolla, CA 92093-0317, U.SA., tAgouron Pharmaceuticals, Inc., San Diego, CA 92121, USA, and fThe Whittier Institute, La Jolla, CA 92037, USA. (Received August lO, 1993) Summary During the past decade numerous advances have been made in understanding the structure, mechanism and clinical properties of dihydropteridine reductase. An attempt is made here to delineate the current status of this essential enzyme by describing its structural features, its kinetic mechanism, the cloning and expression of both rat and human enzyme forms, the solution of their crystal structures, their classifica­ tion as members of a large family of short chain dehydrogenases, and finally a brief description is included indicating how current molecular biological applications have allowed the clinical definition of the aberrant form of phenylketonuria caused by a defective reductase. Key words: Dihydropteridine reductase, Quinonoid dihydrobiopterin, Crystal structure, Aberrant PKU, Gene expression, Mutagenesis Introduction and history in their heterocyclic nucleus of many centers for protonation, which often influence binding and reac­ Naturally occurring pteridines, which usually con­ tivity. Important metabolic functions of conjugated tain 2-amino and 4-hydroxyl substituents can be sep­ pteridine-mediated biological reactions include the arated into two distinct classes. One class contains one-carbon insertion reactions fundamental to pu­ the pterins of the folic acid series which possess rine biosynthesis (4.
    [Show full text]
  • One Scaffold, Three Binding Modes: Novel and Selective Pteridine Reductase 1 Inhibitors Derived from Fragment Hits Discovered by Virtual Screening†
    4454 J. Med. Chem. 2009, 52, 4454–4465 DOI: 10.1021/jm900414x One Scaffold, Three Binding Modes: Novel and Selective Pteridine Reductase 1 Inhibitors Derived from Fragment Hits Discovered by Virtual Screening† Chidochangu P. Mpamhanga, Daniel Spinks, Lindsay B. Tulloch, Emma J. Shanks, David A. Robinson, Iain T. Collie, Alan H. Fairlamb, Paul G. Wyatt, Julie A. Frearson, William N. Hunter, Ian H. Gilbert, and Ruth Brenk* Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K. Received March 31, 2009 The enzyme pteridine reductase 1 (PTR1) is a potential target for new compounds to treat human African trypanosomiasis. A virtual screening campaign for fragments inhibiting PTR1 was carried out. Two novel chemical series were identified containing aminobenzothiazole and aminobenzimidazole scaffolds, respectively. One of the hits (2-amino-6-chloro-benzimidazole) was subjected to crystal structure analysis and a high resolution crystal structure in complex with PTR1 was obtained, confirming the predicted binding mode. However, the crystal structures of two analogues (2-amino- benzimidazole and 1-(3,4-dichloro-benzyl)-2-amino-benzimidazole) in complex with PTR1 revealed two alternative binding modes. In these complexes, previously unobserved protein movements and water-mediated protein-ligand contacts occurred, which prohibited a correct prediction of the binding modes. On the basis of the alternative binding mode of 1-(3,4-dichloro-benzyl)-2-amino-benzimidazole, derivatives
    [Show full text]
  • Evidence of Pyrimethamine and Cycloguanil Analogues As Dual Inhibitors of Trypanosoma Brucei Pteridine Reductase and Dihydrofolate Reductase
    pharmaceuticals Article Evidence of Pyrimethamine and Cycloguanil Analogues as Dual Inhibitors of Trypanosoma brucei Pteridine Reductase and Dihydrofolate Reductase Giusy Tassone 1,† , Giacomo Landi 1,†, Pasquale Linciano 2,† , Valeria Francesconi 3 , Michele Tonelli 3 , Lorenzo Tagliazucchi 2 , Maria Paola Costi 2 , Stefano Mangani 1 and Cecilia Pozzi 1,* 1 Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018–2022, University of Siena, via Aldo Moro 2, 53100 Siena, Italy; [email protected] (G.T.); [email protected] (G.L.); [email protected] (S.M.) 2 Department of Life Science, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy; [email protected] (P.L.); [email protected] (L.T.); [email protected] (M.P.C.) 3 Department of Pharmacy, University of Genoa, Viale Benedetto XV n.3, 16132 Genoa, Italy; [email protected] (V.F.); [email protected] (M.T.) * Correspondence: [email protected]; Tel.: +39-0577-232132 † These authors contributed equally to this work. Abstract: Trypanosoma and Leishmania parasites are the etiological agents of various threatening Citation: Tassone, G.; Landi, G.; neglected tropical diseases (NTDs), including human African trypanosomiasis (HAT), Chagas disease, Linciano, P.; Francesconi, V.; Tonelli, and various types of leishmaniasis. Recently, meaningful progresses in the treatment of HAT, due to M.; Tagliazucchi, L.; Costi, M.P.; Trypanosoma brucei (Tb), have been achieved by the introduction of fexinidazole and the combination Mangani, S.; Pozzi, C. Evidence of therapy eflornithine–nifurtimox. Nevertheless, due to drug resistance issues and the exitance of Pyrimethamine and Cycloguanil animal reservoirs, the development of new NTD treatments is still required.
    [Show full text]
  • Methylated Spirits: Epigenetic Hypotheses of Psychiatric Disorders
    Trends in Psychopharmacology Methylated Spirits: Epigenetic Hypotheses of Psychiatric Disorders Stephen M. Stahl, MD, PhD NEW TREND IN various brain circuits and creating risk for develop- PSYCHOPHARMACOLOGY ing a symptom of a mental illness. Now comes the Our spirits may be regulated by the methylation role of epigenetic actions in mental illnesses. If nor- of our genes. Methylation, acetylation, and other mal genes make normal gene products but at the biochemical processes are the molecular switches wrong time, either being epigenetically expressed for turning genes on and off. There is evidence in neurons when they should be silenced or epi- now that certain behaviors, feelings, and psychiat- genetically silenced in neurons when they should ric symptoms may be modified by turning various be expressed, particularly under the influence of genes on or off. If classical genetics is the sequence environmental factors and stress, this, too, can of DNA that is inherited, then epigenetics is a par- contribute to inefficient information processing in allel process determining whether a given gene brain circuits, increasing the chance of develop- (ie, a sequence of DNA coding for transcription) is ing symptoms of a psychiatric disorder. Here we expressed into its RNA or is silenced. Epigenetics describe the role of epigenetics and methylomics is now entering psychiatry with the hypothesis (methylating or demethylating upstream genes that normal genes as well as risk genes can both and downstream molecules) in various psychiatric contribute to a mental disorder. That is, it has long disorders, emphasizing schizophrenia, and demon- been hypothesized that when “abnormal” genes strate whether your spirits can be truly methylated.
    [Show full text]
  • New Benzimidazole Derivatives As Inhibitors of Pteridine Reductase 1: Design, Molecular Docking Study and ADMET Prediction
    Journal of Applied Pharmaceutical Science Vol. 10(09), pp 030-039, September, 2020 Available online at http://www.japsonline.com DOI: 10.7324/JAPS.2020.10904 ISSN 2231-3354 New benzimidazole derivatives as inhibitors of Pteridine reductase 1: Design, molecular docking study and ADMET prediction Shraddha Phadke1*, Rakesh Somani2, Devender Pathak3 1Dr. L. H. Hiranandani College of Pharmacy, Thane, India. 2D. Y. Patil University School of Pharmacy, Navi Mumbai, India. 3Pharmacy College Saifai, Uttar Pradesh University of Medical Sciences, Etawah, India. ARTICLE INFO ABSTRACT Received on: 23/04/2020 Pteridine reductase 1 (PTR1) is a unique enzyme required for survival of Leishmania species, a causative organism for Accepted on: 14/06/2020 the disease leishmaniasis. We herein report the design, docking, and Absorption, Distribution, Metabolism, Excretion, Available online: 05/09/2020 Toxicity (ADMET) prediction studies of 2-substituted-5-[(6-substituted-1H-benzimidazol-2yl)methyl]azole derivatives (B1–B14) as PTR1 inhibitors. Molecular docking studies showed good binding interaction of the compounds with the active site of pteridine reductase from Leishmania Major, with compounds B5 and B12 showing docking scores Key words: of −61.5232 and −62.5897, respectively, which were comparable with the original ligand, dihydrobiopterin. Large Pteridine reductase 1, substituents on the azole ring, as well as substitutions on sixth position of the benzimidazole ring, were found to be leishmaniasis, benzimidazole favorable for interaction with PTR1 active site. Physicochemical properties, bioactivity prediction, and toxicity profiles derivatives, docking studies, of the compounds were studied using the Molinspiration and admetSAR web servers. All compounds followed Lipinski’s ADMET, druglikeness. rule of five and can be considered as good oral candidates.
    [Show full text]
  • Discovery of Potent Pteridine Reductase Inhibitors to Guide Antiparasite Drug Development
    Discovery of potent pteridine reductase inhibitors to guide antiparasite drug development Antonio Cavazzuti*, Giuseppe Paglietti†, William N. Hunter‡, Francisco Gamarro§, Sandra Piras†, Mario Loriga†, Sergio Alleca†, Paola Corona†, Karen McLuskey‡, Lindsay Tulloch‡, Federica Gibellini*‡, Stefania Ferrari*, and Maria Paola Costi*¶ *Dipartimento di Scienze Farmaceutiche, Universita`di Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy; †Dipartimento Farmaco Chimico Tossicologico, Universita`degli Studi di Sassari, via Muroni 23/a 07100 Sassari, Italy; ‡Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, United Kingdom; and §Instituto de Parasitologia y Biomedicina ‘‘Lopez-Neyra,’’ Consejo Superior de Investigaciones Cientificas, Parque Tecnolo´gico de Ciencias de la Salud, Avenida del Conocimiento s.n., 18100 Armilla, Granada, Spain Edited by Robert M. Stroud, University of California, San Francisco, CA, and approved November 26, 2007 (received for review May 10, 2007) Pteridine reductase (PTR1) is essential for salvage of pterins by Because trypanosomatids are auxotrophic for folates and pterins, parasitic trypanosomatids and is a target for the development of the inhibition of the enzymes depending on them should provide improved therapies. To identify inhibitors of Leishmania major and suitable treatments. However, antifolates are not used in the Trypanosoma cruzi PTR1, we combined a rapid-screening strategy therapy of trypanosomatid infections mainly because of
    [Show full text]
  • Drug Discovery Against Leishmaniasis
    Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 265 Drug discovery against leishmaniasis Bio- and chemoinformatic guided strategies for target evaluation and hit identification ELISABET VIKEVED ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6192 ISBN 978-91-513-0521-9 UPPSALA urn:nbn:se:uu:diva-368499 2019 Dissertation presented at Uppsala University to be publicly examined in A1:107a, BMC, Husargatan 3, Uppsala, Friday, 1 February 2019 at 09:15 for the degree of Doctor of Philosophy (Faculty of Pharmacy). The examination will be conducted in English. Faculty examiner: Professor David Horn (The Wellcome Trust Centre for Anti-Infectives Research, School of Life Sciences, University of Dundee). Abstract Vikeved, E. 2019. Drug discovery against leishmaniasis. Bio- and chemoinformatic guided strategies for target evaluation and hit identification. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 265. 67 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-513-0521-9. Leishmaniasis is a neglected tropical disease mainly affecting poor people in developing countries. It is caused by infections of flagellated protozoa belonging to genus Leishmania. The few available drugs are associated with problems such as low effectiveness, severe side effects and resistance development. The overall aim of this thesis is to aid in drug discovery against leishmaniasis – primarily using bio- and chemoinformtic approaches. In the first part of the thesis potential drug targets in Leishmania parasites were identified and hits against these targets were thereafter suggested. In paper I bioinformatics together with experimental work were used to evaluate lateral gene transfer (LGT) in genus Leishmania. LGTs of prokaryote origin often lack human homologs, and are therefore hypothesized to be valuable drug targets.
    [Show full text]
  • Gunther Stent, Generalist, Feted at 80 Chromosome Mystery Solved
    Transcript MCB Spring 2005 • Vol. 8, No. 1 Newsletter for Members and Alumni of the Department of Molecular & Cell Biology at the University of California, Berkeley Gunther Stent, Generalist, Chromosome Feted at 80 Mystery Solved Neurologist Oliver Sacks, chemist Manfred Few sights are as awe-inspiring as a cell in Eigen and biologist Sydney Brenner were anaphase. Seen through the microscope, the among the scientific notables who gathered replicated chromosomes, having lined up in Koshland Hall on a sunny April Saturday neatly along the midline of the dividing cell to celebrate the life and work of Professor like a row of tiny X’s, are simultaneously Emeritus Gunther Stent. The rare congress of yanked apart. Each X splits into two sideways luminaries and Nobel-prizewinners from V’s careening in opposite directions, folded diverse fields was intended to represent at the middle like a running back receiving a Stent’s wide-ranging interests and contribu- flying tackle. It all happens in the blink of an tions over the course of his career, which has eye in a space smaller than a speck of dust. lasted more than half a century. The orderly segregation of chromo- Organizers Michael Botchan and David somes is absolutely essential to ensure that Weisblat originally wanted the symposium to Gunther Stent every cell has a complete set of genes. Errors coincide with Stent’s 80th birthday last year, in segregation can sometimes lead to cancer but coordinating the visits of so many top sci- or birth defects. Yet how every cell pulls this entists proved more challenging than expect- influenced by physicist Erwin Schrödinger’s off without a hitch nearly every time is poor- ed, Botchan says.
    [Show full text]