G Protein-coupled Receptors in Drug Discovery

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ISBN: 9780824725730 | 0824725735
Cover: Hardcover
Copyright: 7/11/2005

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The broad range of G protein-coupled receptors (GPCRs) encompasses all areas of modern medicine and have an enormous impact on the process of drug development. Using disease-oriented methods to cover everything from screening to expression and crystallization, G Protein-Coupled Receptors in Drug Discoverydescribes the physiological roles of GPCRs and their involvement in various human diseases. The book presents current approaches in drug discovery that include target selection, establishment of screening and functional assays. It also covers recombinant GPCR expression for drug screening and structural biology, different methods for structural characterization of GPCRs, and the importance of bioinformatics. The book has been carefully edited to avoid overlapping information, some duplication has been intentionally permitted so that each chapter can function as an independent unit. Providing in-depth discussions on structure and dynamics of GPCRs, this book outlines the importance of the GPCRs to drug discovery in general and drug targets specifically. Daniel E. Levy, editor of the Drug Discovery Series, is the founder of DEL BioPharma, a consulting service for drug discovery programs. He also maintains a blog that explores organic chemistry.

Chapter 1 Introduction

(2)

Kenneth H. Lundstrom and Mark L. Chiu

Abstract

(1)

1.1 Scope of Book

(1)

1.2 Summary

(1)

Chapter 2 Biology of G Protein-Coupled Receptors

(12)

Kenneth H. Lundstrom

Abstract

(1)

2.1 Introduction

(1)

2.2 Families of GPCRs

(1)

2.3 Coupling to G Proteins

(1)

2.4 GPCR Desensitization

(1)

2.5 Other Signaling Pathways

(2)

2.6 Trafficking of GPCRs

(1)

2.7 Resensitization

(1)

2.8 Conclusions

(1)

References

(4)

Chapter 3 G Protein-Coupled Receptors as Targets for Drug Discovery

(22)

Timothy A. Esbenshade

Abstract

(1)

3.1 Introduction

(1)

3.2 GPCR Family Overview

(3)

3.3 GPCR Tractability: Current Therapeutics

(3)

3.4 GPCR Drug Discovery

(7)

3.4.1 GPCR Target Discovery and Selection

(6)

3.4.1.1 Bioinformatics Approaches for GPCR Discovery

(1)

3.4.1.2 GPCR Localization

(1)

3.4.1.3 GPCR Target Validation

(3)

3.4.1.4 GPCR Druggability

(1)

3.4.2 Lead Optimization

(1)

3.5 Novel GPCR Features and Impact on Drug Discovery Approaches

(3)

3.5.1 Orphan GPCRs

(1)

3.5.2 GPCR Oligomerization

(2)

3.6 Summary

(1)

References

(5)

Chapter 4 G Protein-Coupled Receptors as Cardiovascular Drug Targets

(16)

Mika Scheinin and Amir Snapir

Abstract

(1)

4.1 Cardiovascular Physiology, Pharmacology and Therapeutics

(4)

4.2 Drugs in Development and Novel Drug Targets

(3)

4.3 Receptor Subtypes as Novel Targets

(2)

4.4 Receptor Gene Polymorphisms

(1)

4.5 Concluding Remarks

(1)

References

(4)

Chapter 5 G Protein-Coupled Receptors and Cancer

(32)

Martine J. Smit and Remko A. Bakker

Abstract

(1)

5.1 Introduction

(1)

5.2 Family A GPCRs

(16)

5.2.1 Monoaminergic Receptors

(7)

5.2.1.1 Lipid Messenger Receptors

(1)

5.2.1.2 Peptidergic Receptors

(4)

5.2.1.3 Chemokine Receptors

(1)

5.2.1.4 Purinergic Receptors

(1)

5.2.2 Family C GPCRs

(1)

5.2.2.1 Metabotropic Glutamate Receptors

(1)

5.2.2.2 Calcium Sensing Receptors

(1)

5.2.3 Frizzled/Smoothened Family of GPCRs

(6)

5.2.3.1 Frizzled Receptors

(4)

5.2.3.2 Smoothened Receptors

(2)

5.2.4 Virally Encoded GPCRs

(2)

5.2.5 Orphan GPCRs

(1)

5.3 Conclusions

(1)

Acknowledgments

(1)

References

(13)

Chapter 6 G Protein-Coupled Receptors in Metabolic Disease

(24)

Regina M. Reilly and Christine A. Collins

Abstract

(1)

6.1 Introduction

(1)

6.2 Central Mediation of Feeding and Energy Homeostasis

(4)

6.2.1 Melanocortin System

(1)

6.2.2 Cannabinoid System

(1)

6.2.3 Ghrelin Receptor

(1)

6.2.4 Melanin-Concentrating Hormone Receptors

(1)

6.2.5 Serotonergic System

(1)

6.2.6 Orexin System

(1)

6.2.7 Potential Emerging Targets for Drug Discovery in Metabolic Disease

(1)

6.3 Peripheral Signals Affecting Nutrient Sensing and Utilization

(7)

6.3.1 Satiety and Glucose Homeostasis

(6)

6.3.1.1 Cholecystokinin System

(3)

6.3.1.2 PP-Fold Peptide System

(1)

6.3.1.3 Calcitonin Receptors

(1)

6.3.1.4 Glucagon Receptor Family

(1)

6.3.1.5 Glucose-Dependent Insulinotropic Polypeptide Receptor

(1)

6.3.2 Peripheral Energy Metabolism

(1)

6.3.2.1 β3-Adrenergic Receptor

(1)

6.3.3 Nutrient Sensing Receptors

(1)

6.4 Conclusions

(1)

References

(12)

Chapter 7 G Protein-Coupled Receptors in CNS Drug Discovery

109

(34)

Rita Raddatz and Deborah S. Hartman

Abstract

109

(1)

7.1 Introduction

110

(2)

7.1.1 Synaptic Transmission and Neurotransmitter Pathways

110

(1)

7.1.2 Neuronal Cell Environment

111

(1)

7.2 Psychiatric Diseases

112

(12)

7.2.1 Schizophrenia

112

(10)

7.2.1.1 Characteristics of Antipsychotic Drugs

117

(3)

7.2.1.2 Exploiting GPCR Families: A Closer Look at Dopamine Receptors

120

(2)

7.2.2 Depression

122

(1)

7.2.3 Anxiety

123

(1)

7.3 Pain and Analgesia

124

(2)

7.3.1 Opioid Receptors

124

(1)

7.3.2 Other GPCRs

125

(1)

7.4 Neurodegeneration

126

(2)

7.4.1 Parkinson's Disease

126

(1)

7.4.2 Alzheimer's Disease

127

(1)

7.4.3 Chemokine Receptors and Neurodegeneration

127

(1)

7.5 Neuroendocrine Function

128

(1)

7.6 Orphan GPCRs in the Central Nervous System

128

(1)

7.6.1 Challenges in Evaluating Orphan GPCRs in the CNS

129

(1)

7.7 Conclusions

129

(1)

References

130

(13)

Chapter 8 Recombinant G Protein-Coupled Receptors for Drug Discovery

143

(16)

Kenneth H. Lundstrom

Abstract

143

(1)

8.1 Introduction

144

(1)

8.1.1 Evaluation of Various Expression Systems in Parallel

144

(1)

8.1.2 Modification of Coding Regions of Target GPCR Genes

144

(1)

8.1.3 Engineering of Fusion Proteins

144

(1)

8.1.4 Receptor Production for Structural Biology Applications

145

(1)

8.2 Cell-Free Translation

145

(1)

8.3 E. coli Expression

146

(1)

8.4 Other Prokaryotic Systems

147

(1)

8.5 Yeast Expression

148

(1)

8.6 Insect Cells

149

(1)

8.7 Mammalian Expression

150

(1)

8.8 Comparison of Expression Systems

151

(3)

8.9 Conclusions

154

(1)

References

154

(5)

Chapter 9 High Throughput Screening Assays for G Protein-Coupled Receptors

159

(32)

Usha Warrior, Sujatha Gopalakrishnan, Jurgen Vanhauwe, and David Burns

Abstract

160

(1)

9.1 Introduction

160

(1)

9.2 Source Material and Assay Diversity

160

(1)

9.3 High Throughput Screening

161

(2)

9.4 Receptor Binding Assays: General Considerations

163

(4)

9.4.1 Heterogeneous Receptor Binding Assays

163

(1)

9.4.2 Homogeneous Receptor Binding Assays

164

(3)

9.4.2.1 Homogeneous Radioactive Binding Assays

164

(1)

9.4.2.2 Homogeneous Non-Radioactive Binding Assays

165

(2)

9.5 Functional GPCR Assays

167

(13)

9.5.1 GTP Binding Assays

168

(1)

9.5.2 cAMP Assays

169

(7)

9.5.2.1 General Principles of cAMP Assays Identifying Active Compounds

170

(1)

9.5.2.2 Antibody-Dependent cAMP Detection Assays

170

(2)

9.5.2.3 Antibody-Free Methods for Measuring cAMP

172

(1)

9.5.2.4 cAMP Biosensor

173

(3)

9.5.3 Intracellular Calcium Assays

176

(3)

9.5.4 Inositol-Triphosphate Assays

179

(1)

9.5.5 Melanophore-Based Receptor Functional Activity

179

(1)

9.6 Inverse Agonists and Constitutive Activities

180

(1)

9.7 Microphysiometer Assays

181

(1)

9.8 GPCR Internalization and Trafficking

181

(1)

9.9 Screening for Modulators of Orphan Receptors

182

(1)

9.10 Conclusions

183

(1)

References

183

(8)

Chapter 10 Molecular Bioinformatics of Receptor Binding and Activation

191

(36)

Kevan P. Willey, Heike Obermann, and James B. Procter

Abstract

192

(1)

10.1 Introduction: Not All 7TMRs are GPCRs

192

(1)

10.2 Receptor Classification by Ligand Size

193

(3)

10.2.1 ABC(DEF) Classification of GPCRs

193

(1)

10.2.2 Four Classes of Ligands: Charged, Simple, Flexible, and Complex

194

(2)

10.3 Ligand Diversity Classification Conforms to Receptor Phylogeny

196

(2)

10.3.1 GRAFS Classification of 7TMRs

196

(1)

10.3.2 Rhodopsin Subfamilies Bind Different Classes of Ligand

197

(1)

10.4 Structural Flexibilities of Membrane Receptors

198

(3)

10.4.1 Lack of Hydrophobic Drive in 7TMRs

198

(1)

10.4.2 Cytochrome C Oxidase, Subunit III

199

(2)

10.4.3 Aquaporin

201

(1)

10.5 Molecular Bioinformatics in Drug Discovery

201

(6)

10.5.1 Rhodopsin Structure Revelations

202

(3)

10.5.2 Virtual Screening

205

(2)

10.6 Sequence and Structural Searches for an Activation Mechanism

207

(4)

10.6.1 TM7 and the NPxxY Motif

207

(2)

10.6.2 TM3 and the DRY Motif

209

(1)

10.6.3 TM3 and the Conserved Cystine Bridge

209

(2)

10.7 The Cysteine Shuffle

211

(3)

10.8 Redox Control of Receptor Activation

214

(4)

10.8.1 Ligands Devoid of Sulfur

214

(2)

10.8.2 Ligands Containing Cysteine

216

(2)

10.9 Smells Rank as the Smallest 7TMR Agonists

218

(4)

10.9.1 Sulfur, Charges, Rings

218

(1)

10.9.2 The Essence of Agonism

219

(3)

10.10 Bioinformatics with Biological Sense

222

(1)

References

222

(5)

Chapter 11 Structures and Dynamics of G Protein-Coupled Receptors

227

(44)

Judith Klein-Seetharaman and Michèle C. Loewen

Abstract

228

(1)

11.1 Introduction

228

(2)

11.2 Structure, Stability, Dynamics and Conformational Changes of Rhodopsin

230

(16)

11.2.1 Early Magnetic Resonance Studies of Chromophore and Protein–Lipid Interactions

230

(1)

11.2.2 Advent of Recombinant Expression and Purification Technology

231

(1)

11.2.3 Rhodopsin Structure via Cysteine Mutagenesis Followed by Biochemical and Biophysical Analyses

232

(5)

11.2.3.1 Cysteine Reactivity as Qualitative Indicator for Structure

233

(2)

11.2.3.2 Distance Constraints by Rates of Disulfide Bond Formation

235

(1)

11.2.3.3 Mobility, Accessibility, and Distance Constraints via Electron Paramagnetic Resonance Spectroscopy

235

(2)

11.2.4 Solid-State Nuclear Magnetic Resonance Applications to Rhodopsin

237

(2)

11.2.4.1 Chromophore Structure and Schiff Base Linkage

237

(1)

11.2.4.2 Other Tertiary Interactions

238

(1)

11.2.5 Solution NMR

239

(5)

11.2.5.1 Protein–Protein Interactions

240

(1)

11.2.5.2 Rhodopsin Structure

241

(1)

11.2.5.3 Conformational Dynamics in Rhodopsin

242

(2)

11.2.6 Crystal Structure and Stability of Dark State Rhodopsin

244

(2)

11.3 Structures, Dynamics, and Conformational Changes of GPCRs

246

(4)

11.3.1 Homology Modeling and GPCR Fragment Studies

246

(2)

11.3.2 Structure and Dynamics of Ligands in Context of Full-Length Receptors

248

(1)

11.3.3 Conformational Changes

248

(1)

11.3.4 Constraints Locking Receptors in Their Inactive Conformations

249

(1)

11.3.5 Consequences of Conformational Changes for GPCR Function

250

(1)

11.4 Conclusions

250

(1)

Acknowledgments

251

(1)

References

251

(20)

Chapter 12 Toward Crystallization of G Protein-Coupled Receptors

271

(26)

Mark L. Chiu and Maria P. MacWilliams

Abstract

271

(1)

12.1 Introduction

272

(2)

12.2 Overexpression and Purification

274

(2)

12.3 Detergent Selection

276

(5)

12.4 Sample Preparation

281

(1)

12.5 Crystallization Methods

282

(1)

12.6 Micelles and Bicelles

283

(1)

12.7 Lipidic Mesophases

284

(1)

12.8 Bicelles, Lipopeptides, and Nanodiscs

285

(1)

12.9 Crystallization

285

(1)

12.10 Case Study: Rhodopsin

286

(2)

12.11 Conclusions

288

(1)

References

288

(9)

Chapter 13 Novel Solid-State NMR Methods for Structural Studies on G Protein-Coupled Receptors

297

(18)

Adam Lange and Marc Baldus

Abstract

297

(1)

13.1 Introduction

298

(1)

13.2 High-Resolution Solid-State NMR

299

(2)

13.3 Sample Preparation

301

(2)

13.4 Applications

303

(4)

13.4.1 Receptor-Bound Conformation of Neurotensin

303

(2)

13.4.2 Elucidating Binding Pathway of Neurotensin

305

(1)

13.4.3 Additional Applications to Membrane Peptides and Proteins

306

(1)

13.5 Conclusions and Outlook

307

(1)

Acknowledgments

308

(1)

References

309

(6)

Chapter 14 Structural Genomics Initiatives

315

(10)

Kenneth H. Lundstrom

Abstract

315

(1)

14.1 Introduction

315

(2)

14.2 Structural Genomics Programs Focusing on Membrane Proteins

317

(3)

14.3 Structural Genomics Initiatives Including GPCRs

320

(1)

14.4 MePNet Approach

321

(2)

14.5 Conclusions

323

(1)

References

323

(2)

Chapter 15 Molecular Basis of Dimerization of Family A G Protein-Coupled Receptors

325

(12)

Graeme Milligan

Abstract

325

(1)

15.1 Introduction

326

(1)

15.2 Quaternary Structures of Class A GPCRs

326

(1)

15.3 Consequences of Dimerization of Family A GPCRs

327

(1)

15.4 Mechanisms of Dimerization of Family A GPCRs

328

(5)

15.4.1 Organization of GPCR Dimers and Oligomers

328

(2)

15.4.2 Contributions of Intra- and Extracellular Domains

330

(1)

15.4.3 Contributions of Transmembrane Domains

331

(2)

15.5 Conclusions

333

(1)

Acknowledgments

333

(1)

References

333

(4)

Chapter 16 Orphan Receptors: Promising Targets for Drug Discovery

337

(20)

Yumiko Saito, Zhiwei Wang, and Olivier Civelli

Abstract

337

(1)

16.1 Introduction

337

(1)

16.2 Search for Endogenous Ligands of Orphan GPCRs

338

(6)

16.3 Example of Deorphanization: MCH System and Its Impact on Drug Discovery

344

(2)

16.4 Conclusions and Perspectives

346

(1)

References

347

(10)

Index

357

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G Protein-coupled Receptors in Drug Discovery

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G Protein-coupled Receptors in Drug Discovery

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