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Book Details
Abstract
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.
Table of Contents
Section Title | Page | Action | Price |
---|---|---|---|
Cover | Cover | ||
Allosterism in Drug Discovery | i | ||
Preface | vii | ||
Dedication | ix | ||
Contents | xi | ||
Chapter 1 - Modulation of Biological Targets Using Allosteric Ligands: Food for Thought | 1 | ||
1.1\rDrug Discovery in the Early 21st Century | 1 | ||
1.2 Allostery: A 50-Year Old Concept | 2 | ||
1.3 Allosteric Drugs: The Right Tool at the Right Time | 6 | ||
1.4 Potential Advantages of Allosteric Modulators Over Orthosteric Ligands… or are They | 7 | ||
1.5 Looking Under the Hood | 10 | ||
1.6 “Pure” PAMs and Ago-PAMs | 14 | ||
1.7 Flat SAR | 15 | ||
1.8 Functional Switches | 18 | ||
1.9 Concluding Remarks | 18 | ||
Acknowledgements | 19 | ||
References | 19 | ||
Chapter 2 - Identifying and Quantifying Allosteric Drug Function | 24 | ||
2.1 Introduction: Receptor Allosterism | 24 | ||
2.2 Unique Effects of Allosteric Antagonists | 25 | ||
2.3 Detecting Allosteric Effect | 27 | ||
2.3.1 Saturation of Effect | 27 | ||
2.3.2 Probe Dependence | 28 | ||
2.4 The Functional Allosteric Receptor Model | 28 | ||
2.5 Negative Allosteric Modulators (NAMs) | 30 | ||
2.5.1 Pharmacologic Resultant Analysis | 32 | ||
2.5.2 PAM-Antagonists | 34 | ||
2.6 Kinetics | 36 | ||
2.7 Conclusions | 37 | ||
References | 37 | ||
Chapter 3 - Targeting Catalytic and Non-Catalytic Functions of Protein Kinases | 40 | ||
3.1 Introduction | 40 | ||
3.2 The Kinase Active State | 42 | ||
3.3 Inactive States: An Opportunity for Selective Targeting | 46 | ||
3.4 Highly Selective Kinase Inhibitors Target Unique Binding Pockets | 47 | ||
3.5 Allosteric Inhibitors | 49 | ||
3.6 Examples: Back Pocket Binders Recognizing a Stable DFG-In Conformation | 51 | ||
3.7 Examples: Back Pocket Binders Recognizing a Stable DFG-Out Conformation | 51 | ||
3.8 Differential Effects of Type I and Type II Inhibitors in Signalling | 54 | ||
3.9 Pseudokinases as Drug Targets | 56 | ||
3.10 Conclusions | 57 | ||
References | 58 | ||
Chapter 4 - Molecular Biology Techniques Applied to GPCR Allosteric and Biased Ligands | 65 | ||
4.1 Introduction | 65 | ||
4.2 Primary HTS Assays for Allosteric Modulators of GPCRs | 68 | ||
4.2.1 Binding Studies for AM Identification and Characterization | 68 | ||
4.2.1.1 Radiolabeled Ligands | 69 | ||
4.2.1.2 Fluorescent Ligands | 71 | ||
4.2.1.3 Library Filtering with FRET-Based DTect-All™ | 72 | ||
4.2.1.4 Other RET-Based Binding Assays | 73 | ||
4.2.2 Functional Tests | 74 | ||
4.2.2.1 Calcium | 78 | ||
4.2.2.2 IP1, IP3, and DAG | 79 | ||
4.2.2.3 cAMP and cGMP | 79 | ||
4.2.2.4 Reporter Assays | 81 | ||
4.2.2.5 RET-Based Techniques | 81 | ||
4.2.2.6 β-Arrestin Monitoring | 82 | ||
4.3 Complementary Assays for AM Characterization | 84 | ||
4.3.1 GTP Gamma S | 84 | ||
4.3.2 Label-Free Assays | 84 | ||
4.4 GPCR Biased Ligands: Concepts and Promises | 86 | ||
4.4.1 Multiparametric Profiling with BRET-Based Biosensors | 87 | ||
4.5 Concluding Remarks | 88 | ||
4.5.1 Combining Technologies to Discover Biased Allosteric Modulators | 88 | ||
4.5.2 Further Considerations | 89 | ||
Conflict of Interest | 90 | ||
Acknowledgements | 90 | ||
References | 90 | ||
Chapter 5 - Examining Allosterism in a Dimeric G-Protein-Coupled Receptor Context | 97 | ||
5.1 G-Protein-Coupled Receptors: Paradigms of Allosteric Machines | 97 | ||
5.2 A Decision to be Made by the Receptor: To Bind a G Protein or to Bind a β-Arrestin | 99 | ||
5.2.1 How GPCRs Recognize G Proteins: The µ-Opioid Receptor as an Example | 99 | ||
5.2.2 Dancing with Another Partner: The β-Arrestin Signalling Pathway | 102 | ||
5.2.3 This Decision Can be Affected by the Allosteric Interactions Between Orthosteric and Allosteric Ligands | 104 | ||
5.3 The Complexity and Versatility that Oligomerisation Imparts to GPCR Signalling | 104 | ||
5.3.1 Metabotropic Glutamate Receptors: Where Dimerization Meets Allosterism | 105 | ||
5.3.1.1 Structure–Function Insights from X-Ray Crystallographic Structures | 107 | ||
5.3.1.2 Structure–Function Insights from Dynamic Approaches | 108 | ||
5.3.1.3 Assessing mGlu Receptor Signalling in a Dimeric Context | 110 | ||
5.3.1.4 Conformational Changes at the TMD Determine mGlu Receptor Activation | 110 | ||
5.3.1.5 mGlu Receptors Can Form Heteromers with Class A GPCRs | 112 | ||
5.4 Getting Help from Mechanistic Mathematical Models: The mGlu Receptor as an Example | 113 | ||
5.4.1 Modelling the Transmission of the Signal Through the ECD | 113 | ||
5.4.2 Modelling Cooperativity Effects Between the ECD and the TMD | 115 | ||
5.5 Concluding Remarks and Future Work | 118 | ||
Appendix | 118 | ||
Appendix A. The Metabotropic Glutamate Receptor Model | 118 | ||
Appendix A1. The Equilibrium Constants of the Model for the VFT Domain | 118 | ||
Appendix A2. The Equilibrium Constants of the Model for the TMD | 119 | ||
Appendix A3. Functional Response: Fraction of Active Receptors | 119 | ||
Appendix A4. The Asymptotes of the Functional Curves: Extracting Pharmacological Information from Geometric Descriptors | 120 | ||
Appendix B. The Operational Model of Allosterism | 120 | ||
Appendix B1. The Asymptotes of the Functional Response | 121 | ||
Appendix B2. A Simplified Operational Model | 122 | ||
Appendix B3. The Relation Between Efficacy and Functional Cooperativity in the Operational Model | 122 | ||
Appendix C. The Operational Model of Allosterism Including Constitutive Receptor Activity | 122 | ||
Appendix C1. The Asymptotes of the Functional Response | 123 | ||
Acknowledgements | 124 | ||
References | 124 | ||
Chapter 6 - A Unifying Approach to the Duality of “Energetic” Versus “Conformational” Formulations of Allosteric Coupling: Mechanistic Implications for GPCR Allostery | 131 | ||
6.1 Introduction | 131 | ||
6.2 Dualism in the Definitions of Allostery | 134 | ||
6.3 Structural Changes and Receptor Allostery | 140 | ||
6.4 Allosteric Coupling as the Result of Probability Distributions of Receptor States | 145 | ||
6.5 Conclusions | 151 | ||
Acknowledgements | 151 | ||
References | 151 | ||
Chapter 7 - mGlu2 Receptor Positive Allosteric Modulators | 156 | ||
7.1 Introduction | 156 | ||
7.2 mGlu2 Receptor Positive Allosteric Modulators | 157 | ||
7.2.1 Medicinal Chemistry of mGlu2 Receptor PAMs | 158 | ||
7.2.1.1 Acetophenones and Indoles | 159 | ||
7.2.1.2 Isoindolones | 159 | ||
7.2.1.3 Benzimidazoles | 160 | ||
7.2.1.4 Cyclic Carbamates | 160 | ||
7.2.1.5 1,2-Dihydrooxazolo[2,3-a]benzimidazoles | 161 | ||
7.2.1.6 2,3-Dihydrooxazolo[3,2-a]pyrimidinones | 162 | ||
7.2.1.7 2,3-Dihydroimidazo[2,1-b]oxazoles | 162 | ||
7.2.1.8 Imidazoimidazolones | 162 | ||
7.2.1.9 Pyridones | 163 | ||
7.2.1.10 Imidazopyridines | 164 | ||
7.2.1.11 Triazolopyridines | 164 | ||
7.2.1.12 Benzotriazoles | 165 | ||
7.2.1.13 (Aza)Benzimidazolones | 166 | ||
7.2.2 mGlu Structure and mGlu2 PAM Binding Modes | 166 | ||
7.3 Conclusions | 167 | ||
References | 168 | ||
Chapter 8 - Muscarinic Receptors Allosteric Modulation | 175 | ||
8.1 Introduction | 175 | ||
8.2 Recent Advances with M1 and M4 Bitopic Ligands | 177 | ||
8.3 Recent Advances with M4 Allosteric Ligands | 179 | ||
8.3.1 Current Efforts Using LY2033298 | 179 | ||
8.3.2 M4 Positive Allosteric Modulators Developed at Vanderbilt University | 180 | ||
8.4 Recent Advances in M1 Positive Allosteric Modulators | 183 | ||
8.4.1 Quinolinone and Quinolizidinone Scaffolds | 183 | ||
8.4.2 Tricyclic Positive Allosteric Modulators | 185 | ||
8.4.3 Indole–Oxindole Scaffolds | 186 | ||
8.5 Recent Advances in M5 Negative and Positive Allosteric Modulation | 187 | ||
8.6 Conclusions | 188 | ||
References | 189 | ||
Chapter 9 - Positive Allosteric Modulators of Opioid Receptors | 194 | ||
9.1 Opioid Receptors and Pain | 194 | ||
9.2 Allosteric Modulation | 195 | ||
9.3 Potential Utility of Opioid Receptor PAMs for Pain Management | 197 | ||
9.4 Endogenous Opioid Signaling | 199 | ||
9.5 Enkephalinase Inhibitors | 200 | ||
9.6 Discovery and Characterization of µ-Opioid Receptor PAMs | 200 | ||
9.7 Structure–Activity Relationship Studies and the Identification of µ-Opioid Receptor SAMs | 208 | ||
9.8 Mount Sinai Chemotype | 208 | ||
9.9 δ-Opioid Receptor Selective PAMs | 211 | ||
9.10 Proposed Binding Site for Opioid Receptor PAMs | 213 | ||
9.11 Discussion and Future Directions | 214 | ||
Acknowledgements | 216 | ||
References | 216 | ||
Chapter 10 - mGlu4 PET Ligands as Enablers of Target Biology Understanding | 220 | ||
10.1 Introduction | 220 | ||
10.1.1 Metabotropic Glutamate Receptor 4 (mGlu4) | 221 | ||
10.1.2 mGlu4 and Parkinson’s Disease | 221 | ||
10.1.3 Positron Emission Tomography (PET) Imaging | 222 | ||
10.2 mGlu4 Ligands | 224 | ||
10.2.1 Orthosteric Agonists and Antagonists | 225 | ||
10.2.2 Allosteric Modulators | 226 | ||
10.2.3 Selection of mGlu4 Ligands | 228 | ||
10.3 Co-Operative Binding Assay | 228 | ||
10.4 Development of mGlu4 PET Ligands | 231 | ||
10.4.1 N-(4-Chloro-3-[11C]methoxyphenyl)picolinamide ([11C]14) | 231 | ||
10.4.2 N-(3-Chloro-4-(4-[18F]fluoro-1,3-dioxoisoindolin-2-yl)phenyl)-2-picolinamide ([18F]18) | 232 | ||
10.4.3 Re-Exploring the N-Phenylpicolinamide Derivatives | 235 | ||
10.4.4 N-(3-([11C]Methylthio)phenyl)picolinamide ([11C]26) | 237 | ||
10.4.5 5-Methyl-N-(4-[11C] methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine ([11C]20) | 240 | ||
10.5 Functional Modulation of GPCRs During Parkinson-Disease-Like Neurodegeneration | 241 | ||
10.6 Conclusions | 242 | ||
Acknowledgements | 242 | ||
References | 243 | ||
Chapter 11 - Allosteric Modulators of Adenosine, P2Y and P2X Receptors | 247 | ||
11.1 Introduction | 247 | ||
11.2 Adenosine Receptor (AR) Allosteric Modulation | 249 | ||
11.2.1 Allosteric Modulators of the A1AR | 250 | ||
11.2.2 Allosteric Modulators of the A2AAR and A2BAR | 252 | ||
11.2.3 Allosteric Modulators of the A3AR | 253 | ||
11.2.4 Mutagenesis of ARs to Locate Residues Involved in Interaction with PAMs | 255 | ||
11.3 P2YR Allosteric Modulation | 255 | ||
11.3.1 NAMs of the P2Y1R | 256 | ||
11.3.2 Allosteric Modulation of the P2Y2R | 257 | ||
11.3.3 Allosteric Modulation of the P2Y4R | 257 | ||
11.3.4 Modulation of the P2Y12R | 257 | ||
11.4 P2XR Allosteric Modulation | 258 | ||
11.4.1 Allosteric Modulation of the P2X2R, P2X3R, and P2X2/3R | 258 | ||
11.4.2 Allosteric Modulation of the P2X4R | 261 | ||
11.4.3 Allosteric Modulation of the P2X7R | 261 | ||
11.5 Conclusions | 262 | ||
Abbreviations | 262 | ||
Acknowledgements | 263 | ||
References | 264 | ||
Chapter 12 - Positive Allosteric Modulators of G-Protein-Coupled Receptors that Act via Covalent Mechanisms of Action† | 271 | ||
12.1 Introduction | 271 | ||
12.2 Pharmacology of Compound 2 and BETP | 273 | ||
12.3 Mechanistic Studies with BETP and Compound 2 | 274 | ||
12.4 Covalent Mechanism for BETP and Compound 2 | 275 | ||
12.5 Conclusions | 278 | ||
References | 279 | ||
Chapter 13 - Mechanism of Action of a GluN2C- and GluN2D-Selective NMDA Receptor Positive Allosteric Modulator | 281 | ||
13.1 Introduction | 281 | ||
13.2 Therapeutic Rationale for NMDA Receptor Positive Allosteric Modulators | 285 | ||
13.2.1 Schizophrenia | 285 | ||
13.2.2 Cognitive Enhancement | 286 | ||
13.2.3 Anxiety Disorders | 287 | ||
13.3 Mechanism of Action and Structural Determinants of CIQ | 287 | ||
13.3.1 Mechanism of Action | 287 | ||
13.3.2 Structural Determinants of Activity | 290 | ||
13.4 Off-Target Testing and the Selectivity of CIQ for the NMDA Receptor | 293 | ||
13.5 Pharmacokinetics of CIQ | 293 | ||
13.6 Utility of CIQ as a Pharmacological Probe | 294 | ||
13.6.1 CIQ as a Pharmacological Probe for Fear Acquisition and Fear Extinction | 294 | ||
13.6.2 CIQ as a Pharmacological Probe for Schizophrenia | 295 | ||
13.6.3 CIQ as a Pharmacological Probe to Study Parkinson’s Disease | 297 | ||
13.7 Overview of SAR for the Tetrahydroisoquinoline Class of Compounds Selective for the GluN2C- and GluN2D-Containing NMDA Recep... | 299 | ||
13.8 Conclusions | 300 | ||
Acknowledgements | 301 | ||
References | 301 | ||
Chapter 14 - Development of AMPA Receptor Modulators as Cognition Enhancers | 310 | ||
14.1 Introduction | 310 | ||
14.2 Structure and Function of the AMPA Receptors | 311 | ||
14.3 Chemical Classes of AMPA Receptor Positive Allosteric Modulators | 314 | ||
14.4 Impact of Biostructural Data | 325 | ||
14.5 Summary and Outlook | 328 | ||
References | 329 | ||
Chapter 15 - Allosteric Modulation of Neuronal Nicotinic Acetylcholine Receptors | 334 | ||
15.1 Introduction | 334 | ||
15.2 Nicotinic Receptors Display Broad Expression and Function | 335 | ||
15.3 Nicotinic Receptors are Built for Diversity | 338 | ||
15.4 Explaining Nicotinic Receptor Pharmacology Requires Allostery | 340 | ||
15.5 Nicotinic Receptors Offer Diverse Therapeutic Targets | 342 | ||
15.6 How Can Ligand Site Identification Elucidate Allosteric Mechanisms | 344 | ||
15.6.1 Transmembrane Domain Sites | 345 | ||
15.6.2 Extracellular Inter-Subunit Cleft Sites | 347 | ||
15.7 Total Synthesis | 351 | ||
Acknowledgements | 353 | ||
References | 353 | ||
Chapter 16 - Allosteric Binding in the Serotonin Transporter – Pharmacology, Structure, Function and Potential Use as a Novel Drug Target | 360 | ||
16.1 Introduction | 360 | ||
16.2 The Allosteric Binding Site in SERT | 364 | ||
16.2.1 Early Findings of Allosteric Properties with SERT Ligands | 364 | ||
16.2.2 Location of the Allosteric Binding Site in SERT | 365 | ||
16.2.3 Is Allosteric SERT Modulation Therapeutically Relevant | 369 | ||
16.3 Ligands that Bind to the S2 Site on SERT | 371 | ||
16.4 Conclusions and Perspective | 377 | ||
References | 378 | ||
Chapter 17 - Allosteric Inhibition of Abl Kinase | 381 | ||
17.1 Introduction | 381 | ||
17.2 Structure of Abl Kinase | 382 | ||
17.3 Intramolecular Interactions Regulating Abl Activity | 385 | ||
17.3.1 The Complex Mechanism of Abl Inactivation | 385 | ||
17.3.2 Mechanisms of Abl Activation | 386 | ||
17.4 The Importance of Abl in Cancer Development | 387 | ||
17.4.1 Bcr–Abl Kinase | 387 | ||
17.4.2 The T315I Mutant | 388 | ||
17.5 Bcr–Abl Allosteric Modulation: From ATP Pocket Binders to Allosteric Inhibitors | 389 | ||
17.5.1 Myristate Pocket Binders: Abl Inhibitors | 390 | ||
17.5.1.1 GNF-2 | 391 | ||
17.5.1.2 BO1 | 395 | ||
17.5.2 Myristate Pocket Binders: Abl Activators | 398 | ||
17.6 Conclusions | 400 | ||
References | 400 | ||
Chapter 18 - Allosteric Modulators of Heat Shock Protein 90 (HSP90) | 404 | ||
18.1 Introduction: Molecular Chaperones | 404 | ||
18.2 Heat Shock Protein 90 | 405 | ||
18.3 HSP90 Function | 408 | ||
18.4 HSP90 Inhibitors | 409 | ||
18.4.1 HSP90 Inhibitors that Target the N-Terminus | 411 | ||
18.4.2 C-Terminal Binders | 415 | ||
18.4.3 C-Terminal Modulators | 416 | ||
18.5 Concluding Remarks | 420 | ||
References | 421 | ||
Subject Index | 427 |