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Allosterism in Drug Discovery

Allosterism in Drug Discovery

Dario Doller

(2016)

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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