Allosteric Regulation in Drug Design
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Tyrosine Kinase – Role and Significance in Cancer
Int. J. Med. Sci. 2004 1(2): 101-115 101 International Journal of Medical Sciences ISSN 1449-1907 www.medsci.org 2004 1(2):101-115 ©2004 Ivyspring International Publisher. All rights reserved Review Tyrosine kinase – Role and significance in Cancer Received: 2004.3.30 Accepted: 2004.5.15 Manash K. Paul and Anup K. Mukhopadhyay Published:2004.6.01 Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S Nagar, Mohali, Punjab, India-160062 Abstract Tyrosine kinases are important mediators of the signaling cascade, determining key roles in diverse biological processes like growth, differentiation, metabolism and apoptosis in response to external and internal stimuli. Recent advances have implicated the role of tyrosine kinases in the pathophysiology of cancer. Though their activity is tightly regulated in normal cells, they may acquire transforming functions due to mutation(s), overexpression and autocrine paracrine stimulation, leading to malignancy. Constitutive oncogenic activation in cancer cells can be blocked by selective tyrosine kinase inhibitors and thus considered as a promising approach for innovative genome based therapeutics. The modes of oncogenic activation and the different approaches for tyrosine kinase inhibition, like small molecule inhibitors, monoclonal antibodies, heat shock proteins, immunoconjugates, antisense and peptide drugs are reviewed in light of the important molecules. As angiogenesis is a major event in cancer growth and proliferation, tyrosine kinase inhibitors as a target for anti-angiogenesis can be aptly applied as a new mode of cancer therapy. The review concludes with a discussion on the application of modern techniques and knowledge of the kinome as means to gear up the tyrosine kinase drug discovery process. -
DNA Breakpoint Assay Reveals a Majority of Gross Duplications Occur in Tandem Reducing VUS Classifications in Breast Cancer Predisposition Genes
© American College of Medical Genetics and Genomics ARTICLE Corrected: Correction DNA breakpoint assay reveals a majority of gross duplications occur in tandem reducing VUS classifications in breast cancer predisposition genes Marcy E. Richardson, PhD1, Hansook Chong, PhD1, Wenbo Mu, MS1, Blair R. Conner, MS1, Vickie Hsuan, MS1, Sara Willett, MS1, Stephanie Lam, MS1, Pei Tsai, CGMBS, MB (ASCP)1, Tina Pesaran, MS, CGC1, Adam C. Chamberlin, PhD1, Min-Sun Park, PhD1, Phillip Gray, PhD1, Rachid Karam, MD, PhD1 and Aaron Elliott, PhD1 Purpose: Gross duplications are ambiguous in terms of clinical cohort, while the remainder have unknown tandem status. Among interpretation due to the limitations of the detection methods that the tandem gross duplications that were eligible for reclassification, cannot infer their context, namely, whether they occur in tandem or 95% of them were upgraded to pathogenic. are duplicated and inserted elsewhere in the genome. We Conclusion: DBA is a novel, high-throughput, NGS-based method investigated the proportion of gross duplications occurring in that informs the tandem status, and thereby the classification of, tandem in breast cancer predisposition genes with the intent of gross duplications. This method revealed that most gross duplica- informing their classifications. tions in the investigated genes occurred in tandem and resulted in a Methods: The DNA breakpoint assay (DBA) is a custom, paired- pathogenic classification, which helps to secure the necessary end, next-generation sequencing (NGS) method designed to treatment options for their carriers. capture and detect deep-intronic DNA breakpoints in gross duplications in BRCA1, BRCA2, ATM, CDH1, PALB2, and CHEK2. Genetics in Medicine (2019) 21:683–693; https://doi.org/10.1038/s41436- Results: DBA allowed us to ascertain breakpoints for 44 unique 018-0092-7 gross duplications from 147 probands. -
Design Principles for Regulator Gene Expression in a Repressible Gene
Design of Repressible Gene Circuits: M.E. Wall et al. 1 Design Principles for Regulator Gene Expression in a Repressible Gene Circuit Michael E. Wall1,2, William S. Hlavacek3* and Michael A. Savageau4+ 1Computer and Computational Sciences Division and 2Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA 3Theoretical Biology and Biophysics Group (T-10), Theoretical Division, Mail Stop K710, Los Alamos National Laboratory, Los Alamos, NM 87545, USA 4Department of Microbiology and Immunology, The University of Michigan Medical School, Ann Arbor, MI 48109-0620, USA +Current address: Department of Biomedical Engineering, One Shields Avenue, University of California, Davis, CA 95616, USA. *Corresponding author Tel.: +1-505 665 1355 Fax: +1-505 665 3493 E-mail address of the corresponding author: [email protected] Design of Repressible Gene Circuits: M.E. Wall et al. 2 Summary We consider the design of a type of repressible gene circuit that is common in bacteria. In this type of circuit, a regulator protein acts to coordinately repress the expression of effector genes when a signal molecule with which it interacts is present. The regulator protein can also independently influence the expression of its own gene, such that regulator gene expression is repressible (like effector genes), constitutive, or inducible. Thus, a signal-directed change in the activity of the regulator protein can result in one of three patterns of coupled regulator and effector gene expression: direct coupling, in which regulator and effector gene expression change in the same direction; uncoupling, in which regulator gene expression remains constant while effector gene expression changes; or inverse coupling, in which regulator and effector gene expression change in opposite directions. -
Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model
Downloaded from http://www.jimmunol.org/ by guest on September 25, 2021 T + is online at: average * The Journal of Immunology , 34 of which you can access for free at: 2016; 197:1477-1488; Prepublished online 1 July from submission to initial decision 4 weeks from acceptance to publication 2016; doi: 10.4049/jimmunol.1600589 http://www.jimmunol.org/content/197/4/1477 Molecular Profile of Tumor-Specific CD8 Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. Waugh, Sonia M. Leach, Brandon L. Moore, Tullia C. Bruno, Jonathan D. Buhrman and Jill E. Slansky J Immunol cites 95 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2016/07/01/jimmunol.160058 9.DCSupplemental This article http://www.jimmunol.org/content/197/4/1477.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 25, 2021. The Journal of Immunology Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. -
Integrated Computational Approaches and Tools for Allosteric Drug Discovery
International Journal of Molecular Sciences Review Integrated Computational Approaches and Tools for Allosteric Drug Discovery Olivier Sheik Amamuddy 1 , Wayde Veldman 1 , Colleen Manyumwa 1 , Afrah Khairallah 1 , Steve Agajanian 2, Odeyemi Oluyemi 2, Gennady M. Verkhivker 2,3,* and Özlem Tastan Bishop 1,* 1 Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South Africa; [email protected] (O.S.A.); [email protected] (W.V.); [email protected] (C.M.); [email protected] (A.K.) 2 Graduate Program in Computational and Data Sciences, Keck Center for Science and Engineering, Schmid College of Science and Technology, Chapman University, One University Drive, Orange, CA 92866, USA; [email protected] (S.A.); [email protected] (O.O.) 3 Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA 92618, USA * Correspondence: [email protected] (G.M.V.); [email protected] (Ö.T.B.); Tel.: +714-516-4586 (G.M.V.); +27-46-603-8072 (Ö.T.B.) Received: 25 December 2019; Accepted: 21 January 2020; Published: 28 January 2020 Abstract: Understanding molecular mechanisms underlying the complexity of allosteric regulation in proteins has attracted considerable attention in drug discovery due to the benefits and versatility of allosteric modulators in providing desirable selectivity against protein targets while minimizing toxicity and other side effects. The proliferation of novel computational approaches for predicting ligand–protein interactions and binding using dynamic and network-centric perspectives has led to new insights into allosteric mechanisms and facilitated computer-based discovery of allosteric drugs. Although no absolute method of experimental and in silico allosteric drug/site discovery exists, current methods are still being improved. -
Enzyme Regulation What Factors Influence Enzymatic Activity?
12/3/13 Enzyme Regulation What Factors Influence Enzymatic Activity? Principle means of regulating enzyme activity • Reversible, non-covalent (allosteric and simple- MM) – typically small molecules • Reversible, covalent • Protein-Protein interactions • Zymogen activation • Protein expression and degradation • Availability (both of enzyme and substrate) Reversible Noncovalent: Reversible Noncovalent Allosteric Simple activation and inhibition by small molecules – Action at "another site" substrate, natural regulators of enzymes Enzymes situated at key steps in metabolic pathways are modulated by allosteric effectors MM kinetics Km, Vmax – competitive, non These effectors are usually produced elsewhere in competitive… the pathway Effectors may be feed-forward activators or Substrate inhibition or activation feedback inhibitors Kinetics are sigmoid ("S-shaped") The availability of substrates and cofactors usually determines how fast the reaction goes As product accumulates, the apparent rate of the enzymatic reaction will decrease General Features of Allosteric Regulation Allosteric activation/inhibition In most metabolic pathways there is at least 1 key enzyme Usually these pacemaker enzymes are in the first committed step in the pathway. Many times regulated by both feed forward and feedback mechanisms A B C D E Sigmoid v versus [S] plot. The dotted line represents the hyperbolic plot characteristic of normal Michaelis=Menten kinetics. 1 12/3/13 Allosteric activation/inhibition Reversible Covalent In most metabolic pathways there is at -
Tyrosine Kinases
KEVANM SHOKAT MINIREVIEW Tyrosine kinases: modular signaling enzymes with tunable specificities Cytoplasmic tyrosine kinases are composed of modular domains; one (SHl) has catalytic activity, the other two (SH2 and SH3) do not. Kinase specificity is largely determined by the binding preferences of the SH2 domain. Attaching the SHl domain to a new SH2 domain, via protein-protein association or mutation, can thus dramatically change kinase function. Chemistry & Biology August 1995, 2:509-514 Protein kinases are one of the largest protein families identified, This is a result of the overlapping substrate identified to date; over 45 new members are identified specificities of many tyrosine kinases, which makes it each year. It is estimated that up to 4 % of vertebrate pro- difficult to dissect the individual signaling pathways by teins are protein kinases [l].The protein kinases are cate- scanning for unique target motifs [2]. gorized by their specificity for serineithreonine, tyrosine, or histidine residues. Protein tyrosine kinases account for The apparent promiscuity of individual tyrosine kinases roughly half of all kinases. They occur as membrane- is a result of their unique structural organization. bound receptors or cytoplasmic proteins and are involved Enzyme specificity is typically programmed by one in a wide variety of cellular functions, including cytokine binding site, which recognizes the substrate and also con- responses, antigen-dependent immune responses, cellular tains exquisitely oriented active-site functional groups transformation by RNA viruses, oncogenesis, regulation that help to lower the energy of the transition state for of the cell cycle, and modification of cell morphology the conversion of specific substrates to products.Tyrosine (Fig. -
Structure and Evolution of Protein Allosteric Sites
Structure and evolution of protein allosteric sites by Alejandro Panjkovich Thesis submitted to Universitat Aut`onoma de Barcelona in partial fulfillment of the requirements for the degree of Doctor of Philosophy Director - Prof. Xavier Daura Tesi Doctoral UAB/ANY 2013 Ph.D. Program - Protein Structure and Function Institut de Biotecnologia i Biomedicina caminante, no hay camino, se hace camino al andar Antonio Machado,1912 Acknowledgements First of all I would like to thank my supervisor and mentor Prof. Xavier Daura for his consistent support and trust in my work throughout these years. Xavi, I deeply appreciate the freedom you gave me to develop this project while you were still carefully aware of the small details. Working under your supervision has been a rich and fulfilling experience. Of course, thanks go as well to current and past members of our institute, especially Rita Rocha, Pau Marc Mu˜noz,Oscar Conchillo, Dr. Mart´ınIndarte, Dr. Mario Ferrer, Prof. Isidre Gibert, Dr. Roman Affentranger and Dr. Juan Cedano for their technical and sometimes philo- sophical assistance. Help from the administrative staff was also significant, I would like to thank in particular Eva, Alicia and Miguel who where always ready to help me in sorting out unexpected bureaucratic affairs. I would also like to thank Dr. Mallur Srivatasan Madhusudhan and his group (especially Kuan Pern Tan, Dr. Minh Nguyen and Binh Nguyen), and also Dr. Gloria Fuentes, Cassio Fernandes, Youssef Zaki, Thijs Kooi, Rama Iyer, Christine Low and many others at the Bioinformatics Institute BII - A∗STAR in Singapore for the many interesting discussions and support during my stage over there. -
Understanding Drug-Drug Interactions Due to Mechanism-Based Inhibition in Clinical Practice
pharmaceutics Review Mechanisms of CYP450 Inhibition: Understanding Drug-Drug Interactions Due to Mechanism-Based Inhibition in Clinical Practice Malavika Deodhar 1, Sweilem B Al Rihani 1 , Meghan J. Arwood 1, Lucy Darakjian 1, Pamela Dow 1 , Jacques Turgeon 1,2 and Veronique Michaud 1,2,* 1 Tabula Rasa HealthCare Precision Pharmacotherapy Research and Development Institute, Orlando, FL 32827, USA; [email protected] (M.D.); [email protected] (S.B.A.R.); [email protected] (M.J.A.); [email protected] (L.D.); [email protected] (P.D.); [email protected] (J.T.) 2 Faculty of Pharmacy, Université de Montréal, Montreal, QC H3C 3J7, Canada * Correspondence: [email protected]; Tel.: +1-856-938-8697 Received: 5 August 2020; Accepted: 31 August 2020; Published: 4 September 2020 Abstract: In an ageing society, polypharmacy has become a major public health and economic issue. Overuse of medications, especially in patients with chronic diseases, carries major health risks. One common consequence of polypharmacy is the increased emergence of adverse drug events, mainly from drug–drug interactions. The majority of currently available drugs are metabolized by CYP450 enzymes. Interactions due to shared CYP450-mediated metabolic pathways for two or more drugs are frequent, especially through reversible or irreversible CYP450 inhibition. The magnitude of these interactions depends on several factors, including varying affinity and concentration of substrates, time delay between the administration of the drugs, and mechanisms of CYP450 inhibition. Various types of CYP450 inhibition (competitive, non-competitive, mechanism-based) have been observed clinically, and interactions of these types require a distinct clinical management strategy. This review focuses on mechanism-based inhibition, which occurs when a substrate forms a reactive intermediate, creating a stable enzyme–intermediate complex that irreversibly reduces enzyme activity. -
Spring 2013 Lecture 13-14
CHM333 LECTURE 13 – 14: 2/13 – 15/13 SPRING 2013 Professor Christine Hrycyna INTRODUCTION TO ENZYMES • Enzymes are usually proteins (some RNA) • In general, names end with suffix “ase” • Enzymes are catalysts – increase the rate of a reaction – not consumed by the reaction – act repeatedly to increase the rate of reactions – Enzymes are often very “specific” – promote only 1 particular reaction – Reactants also called “substrates” of enzyme catalyst rate enhancement non-enzymatic (Pd) 102-104 fold enzymatic up to 1020 fold • How much is 1020 fold? catalyst time for reaction yes 1 second no 3 x 1012 years • 3 x 1012 years is 500 times the age of the earth! Carbonic Anhydrase Tissues ! + CO2 +H2O HCO3− +H "Lungs and Kidney 107 rate enhancement Facilitates the transfer of carbon dioxide from tissues to blood and from blood to alveolar air Many enzyme names end in –ase 89 CHM333 LECTURE 13 – 14: 2/13 – 15/13 SPRING 2013 Professor Christine Hrycyna Why Enzymes? • Accelerate and control the rates of vitally important biochemical reactions • Greater reaction specificity • Milder reaction conditions • Capacity for regulation • Enzymes are the agents of metabolic function. • Metabolites have many potential pathways • Enzymes make the desired one most favorable • Enzymes are necessary for life to exist – otherwise reactions would occur too slowly for a metabolizing organis • Enzymes DO NOT change the equilibrium constant of a reaction (accelerates the rates of the forward and reverse reactions equally) • Enzymes DO NOT alter the standard free energy change, (ΔG°) of a reaction 1. ΔG° = amount of energy consumed or liberated in the reaction 2. -
E3 Ubiquitin Ligase SYVN1 Is a Key Positive Regulator for GSDMD
bioRxiv preprint doi: https://doi.org/10.1101/2021.07.21.453219; this version posted July 21, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 E3 ubiquitin ligase SYVN1 is a key positive regulator for 2 GSDMD-mediated pyroptosis 3 4 Yuhua Shi 1,2,#, Yang Yang3,#, Weilv Xu1,#, Wei Xu1, Xinyu Fu1, Qian Lv1, Jie Xia1, 5 Fushan Shi1,2,* 6 1 Department of Veterinary Medicine, College of Animal Sciences, Zhejiang 7 University, Hangzhou 310058, Zhejiang, PR China 8 2 Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, Zhejiang 9 University, Hangzhou 310058, Zhejiang, PR China 10 3 Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of 11 Zhejiang Province, Zhejiang Provincial Engineering Laboratory for Animal Health 12 Inspection & Internet Technology, College of Animal Science and Technology & 13 College of Veterinary Medicine of Zhejiang A&F University, Hangzhou 311300, 14 Zhejiang, China 15 # These authors contributed equally to this work 16 *Corresponding author: Fushan Shi, E-mail: [email protected], Tel: 17 +086-0571-88982275 18 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.07.21.453219; this version posted July 21, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 19 Abstract 20 Gasdermin D (GSDMD) participates in activation of inflammasomes and pyroptosis. 21 Meanwhile, ubiquitination strictly regulates inflammatory responses. However, how 22 ubiquitination regulates Gasdermin D activity is not well understood. -
SNX8 Modulates Innate Immune Response to DNA Virus by Mediating Trafficking and Activation of MITA
RESEARCH ARTICLE SNX8 modulates innate immune response to DNA virus by mediating trafficking and activation of MITA Jin Wei1³, Huan Lian1³, Wei Guo1, Yun-Da Chen1,2, Xia-Nan Zhang1,2, Ru Zang1, Li Zhong1, 1 1 3 1,2 1 Qing Yang , Ming-Ming Hu , Wei-Wei Luo , Hong-Bing Shu *, Shu LiID * 1 Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China, 2 College of Life Sciences, Wuhan University, Wuhan, China, 3 Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China a1111111111 a1111111111 ³ These authors share first authorship on this work. a1111111111 * [email protected] (HBS); [email protected] (SL) a1111111111 a1111111111 Abstract MITA (also called STING) is a central adaptor protein in innate immune response to cyto- solic DNA. Cellular trafficking of MITA from the ER to perinuclear microsomes after DNA OPEN ACCESS virus infection is critical for MITA activation and onset of innate antiviral response. Here we Citation: Wei J, Lian H, Guo W, Chen Y-D, Zhang found that SNX8 is a component of DNA-triggered induction of downstream effector genes X-N, Zang R, et al. (2018) SNX8 modulates innate and innate immune response. Snx8-/- mice infected with the DNA virus HSV-1 exhibited immune response to DNA virus by mediating trafficking and activation of MITA. PLoS Pathog 14 lower serum cytokine levels and higher viral titers in the brains, resulting in higher lethality. (10): e1007336. https://doi.org/10.1371/journal. Mechanistically, SNX8 recruited the class III phosphatylinositol 3-kinase VPS34 to MITA, ppat.1007336 which is required for trafficking of MITA from the ER to perinuclear microsomes.