Allosterism in Drug Discovery (RSC Drug Discovery, 56, Band 56) - Hardcover

Hardcover

ISBN 10: 1782624597 ISBN 13: 9781782624592

Verlag: Royal Society of Chemistry, 2016

Inhaltsangabe

Although the concept of allosterism has been known for over half a century, its application in drug discovery has exploded in recent years. The emergence of novel technologies that enable molecular-level ligand-receptor interactions to be studied in studied in unprecedented detail has driven this trend. This book, written by the leaders in this young research area, describes the latest developments in allosterism for drug discovery.

Bringing together research in a diverse range of scientific disciplines, Allosterism in Drug Discovery is a key reference for academics and industrialists interested in understanding allosteric interactions. The book provides an in-depth review of research using small molecules as chemical probes and drug candidates that interact allosterically with proteins of relevance to life sciences and human disease. Knowledge of these interactions can then be applied in the discovery of the novel therapeutics of the future.

This book will be useful for people working in all disciplines associated with drug discovery in academia or industry, as well as postgraduate students who may be working in the design of allosteric modulators.

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Although the concept of allosterism has been known for over half a century, its application in drug discovery has exploded in recent years. The emergence of novel technologies that enable molecular-level ligand-receptor interactions to be studied in unprecedented detail has driven this trend. This book, written by leaders in this research area, describes the latest developments in allosterism for drug discovery.

Bringing together research in a diverse range of scientific disciplines, Allosterism in Drug Discovery is a key reference for academics and industrialists interested in understanding allosteric interactions. The book provides an in-depth review of research using small molecules as chemical probes and drug candidates that interact allosterically with proteins of relevance to life sciences and human disease. Knowledge of these interactions can then be applied in the discovery of the novel therapeutics of the future.

This book will be useful for people working in all disciplines associated with drug discovery in academia or industry, as well as postgraduate students who may be working in the design of allosteric modulators.

Aus dem Klappentext

Although the concept of allosterism has been known for over half a century, its application in drug discovery has exploded in recent years. The emergence of novel technologies that enable molecular-level ligand-receptor interactions to be studied in unprecedented detail has driven this trend. This book, written by leaders in this research area, describes the latest developments in allosterism for drug discovery.

Bringing together research in a diverse range of scientific disciplines, Allosterism in Drug Discovery is a key reference for academics and industrialists interested in understanding allosteric interactions. The book provides an in-depth review of research using small molecules as chemical probes and drug candidates that interact allosterically with proteins of relevance to life sciences and human disease. Knowledge of these interactions can then be applied in the discovery of the novel therapeutics of the future.

This book will be useful for people working in all disciplines associated with drug discovery in academia or industry, as well as postgraduate students who may be working in the design of allosteric modulators.

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Allosterism in Drug Discovery

By Dario Doller

The Royal Society of Chemistry

Copyright © 2017 The Royal Society of Chemistry
All rights reserved.

ISBN: 978-1-78262-459-2

Contents

Chapter 1 Modulation of Biological Targets Using Allosteric Ligands: Food for Thought Dario Doller and Xinyan Huang, 1, 
Chapter 2 Identifying and Quantifying Allosteric Drug Function Terry Kenakin, 24, 
Chapter 3 Targeting Catalytic and Non-Catalytic Functions of Protein Kinases Susanne Müller and Stefan Knapp, 40, 
Chapter 4 Molecular Biology Techniques Applied to GPCR Allosteric and Biased Ligands Mélanie Frauli, Christel Franchet, Ismet Dorange, Arturo Mancini, Billy Breton and Stephan Schann, 65, 
Chapter 5 Examining Allosterism in a Dimeric G-Protein-Coupled Receptor Context Jesús Giraldo, Jordi Ortiz, James Dalton and Bin Zhou, 97, 
Chapter 6 A Unifying Approach to the Duality of "Energetic" Versus "Conformational" Formulations of Allosteric Coupling: Mechanistic Implications for GPCR Allostery H. Ongun Onaran and Tommaso Costa, 131, 
Chapter 7 mGlu2 Receptor Positive Allosteric Modulators A. A. Trabanco, J. M. Cid and G. Tresadern, 156, 
Chapter 8 Muscarinic Receptors Allosteric Modulation Bruce J. Melancon and Corey R. Hopkins, 175, 
Chapter 9 Positive Allosteric Modulators of Opioid Receptors Kristin L. Rockwell and Andrew Alt, 194, 
Chapter 10 mGlu4 PET Ligands as Enablers of Target Biology Understanding Zhaoda Zhang, Pekka Poutiainen and Anna-Liisa Brownell, 220, 
Chapter 11 Allosteric Modulators of Adenosine, P2Y and P2X Receptors Kenneth A. Jacobson and Zhan-Guo Gao, 247, 
Chapter 12 Positive Allosteric Modulators of G-Protein-Coupled Receptors that Act via Covalent Mechanisms of Action Whitney M. Nolte and Philip A. Carpino, 271, 
Chapter 13 Mechanism of Action of a GluN2C- and GluN2D-Selective NMDA Receptor Positive Allosteric Modulator Katie L. Strong, Matthew P. Epplin, Yao Jing, Stephen F. Traynelis and Dennis C. Liotta, 281, 
Chapter 14 Development of AMPA Receptor Modulators as Cognition Enhancers Craig Jamieson and Emma L. Duffy, 310, 
Chapter 15 Allosteric Modulation of Neuronal Nicotinic Acetylcholine Receptors Mark M. Levandoski and Sivaramakrishna Koganti, 334, 
Chapter 16 Allosteric Binding in the Serotonin Transporter – Pharmacology, Structure, Function and Potential Use as a Novel Drug Target Claus J. Loland, Connie Sanchez, Per Plenge, Klaus P. Bøgesø and Benny Bang-Andersen, 360, 
Chapter 17 Allosteric Inhibition of Abl Kinase Anna Lucia Fallacara, Silvia Schenone and Maurizio Botta, 381, 
Chapter 18 Allosteric Modulators of Heat Shock Protein 90 (HSP90) Yen Chin Koay and Shelli McAlpine, 404, 
Subject Index, 427, 

CHAPTER 1

Modulation of Biological Targets Using Allosteric Ligands: Food for Thought

DARIO DOLLER AND XINYAN HUANG

1.1 Drug Discovery in the Early 21st Century

The dawn of the new century found several major pharmaceutical companies facing significant challenges in keeping their pipelines populated with new drugs. For nearly two decades, robust increases in research and development investments had not produced the hoped for number of new medical entities (NMEs) approvals per year. In some therapeutic areas such as diseases of the central nervous system (CNS), and in spite of a growing patient population and major medical needs, only a handful of new drugs were approved during this period, and mostly based on mechanisms already known ("me too" drugs). As a response to this crisis of innovation, and propelled by major discoveries in molecular and cell biology research, in particular in the areas of oncology and immunology, a chemically broad range of new therapeutic modalities emerged, such as antibodies, proteins, nucleic acids, vaccines, cell, or gene therapies. These are generally grouped under the denomination "biologics", to differentiate them from "small molecules". Drugs in the latter group have historically been mostly thought of as acting competitively with endogenous ligands, binding at their target receptors in a model that became known as "lock and key". These two types of drugs differ in terms of a number of attributes, such as molecular weight, preparation, characterization of the active pharmaceutical ingredient (API), physicochemical properties, possible route of administration, pharmacokinetic distribution, metabolism, clearance mechanisms, drug-drug interactions, dosing regimen, safety and toxicology, antigenicity and hypersensitivity, and pharmacology – including side effects. A comparison of these attributes highlights some of the challenges associated with the development of biologics as drugs. (Table 1.1) It also begs the question whether new strategies could be discovered to modulate drug targets with a different type of small molecules. This is, in essence, the promise of what allosteric modulators might do.

1.2 Allostery: A 50-Year Old Concept

Broadly, allostery has been defined as an indirect interaction between topographically distinct binding sites in a protein, mediated by a conformational change. Monod and Jacob used the term for the first time in the printed version of the Proceedings of the 26th Cold Spring Harbor Symposium on Quantitative Biology entitled "Cellular Regulatory Mechanisms" in 1961, in the general discussion written as a conclusion of the conference. The earliest appearance of the term "allostery" in a publication listed in PubMed dates to more than half a century ago. Since then, the concept has evolved and its use expanded notably. Today, allosterism is considered an inherent property of all dynamic proteins and other macromolecules of biological relevance. Examples of important drugs exist that are allosteric modulators of diverse targets such as ion channels, G protein-coupled receptors (GPCRs), and enzymes. Benzodiazepines, one of the earlier drug classes with major impact on society, act as negative (flumazenil, 1) or positive (diazepam, 2; flunitrazepam, 3) allosteric modulators of gamma aminobutyric acid A (GABA) ion channels. The first inhibitors of human immunodeficiency virus reverse transcriptase enzyme (HIVRT) useful in the treatment of AIDS were nucleoside analogs. These compounds act competitively and inhibit the binding of the appropriate deoxynucleotide triphosphate (ATP, TTP, GTP, or CTP) to the reverse transcriptase (RT) enzyme. Nevirapine (4) and efavirenz (5) are non-nucleoside RT inhibitors (NNRTIs). Both nucleoside and non-nucleoside RTIs inhibit the same target, the reverse transcriptase enzyme, an essential viral enzyme which transcribes viral RNA into DNA. Unlike nucleoside RTIs, which bind at the enzyme's active site, NNRTIs bind allosterically at a distinct site away from the active site called the NNRTI pocket. Maraviroc (6) is another antiretroviral drug used in the treatment of HIV infection, which works through a negative allosteric modulation (NAM) mechanism inhibiting the cell-surface chemokine CCR5 receptor. The chemokine receptor CCR5 is a co-receptor for most HIV strains, necessary for the entrance of the virus into the host cell. The drug binds to CCR5 and changes its conformation, thus blocking the HIV protein gp120 from associating with the receptor. HIV is then unable to enter human macrophages and T-cells. Cinacalcet (7), a calcimimetic, is a positive allosteric modulator (PAM) of the calcium-sensing receptor (CaSR), which is activated according to the natural rise and fall of endogenous calcium ion levels....

Details zur Ausgabe

• Verlag: Royal Society of Chemistry
• Erscheinungsdatum: 2016
• Sprache: Englisch
• ISBN 10: 1782624597
• ISBN 13: 9781782624592
• Einband: Gebundene Ausgabe
• Auflage: 1
• Anzahl der Seiten: 437
• Herausgeber: Doller Dario
• Kontakt zum Hersteller: Nicht verfügbar
• Verantwortliche Person: Nicht verfügbar