G Protein Coupled Receptors in Drug Discovery presents current approaches in drug discovery that include target selection, establishment of screening and functional assays.

Features:

• Describes the principal mechanisms for signal transduction through activation of GPCRs and their interactions with G proteins and other cellular proteins
• Demonstrates the signal transduction mechanisms in detail with various examples
• Covers specific areas of medicine such as cardiovascular disease, cancer, metabolic disease, and neurodegeneration and psychiatry
• Explores high throughput screening methods for GPCRs that naturally play important roles in drug discovery
• Discusses applied expression systems and in silico methods including application of bioinformatics and molecular modeling as tools to support structural biology approaches
• Provides insight into the structural characterization and dynamics of GPCRs using rhodopsin as a model protein
• Delineates the problems and recent development in crystallization of GPCRs and demonstrates how novel NMR methods can potentially be applied to GPCRs
• Elucidates the importance of dimerization in relation to drug discovery
• Contains a chapter on the continuous de-orphanization process of orphan GPCRs

Contents

Biology of G Protein-Coupled Receptors

• Introduction
• Families of GPCRs
• Coupling to G Proteins
• GPCR Desensitization
• Other Signaling Pathways
• Trafficking of GPCRs
• Resensitization
• Conclusions

G Protein Coupled Receptors as Targets for Drug Discovery

• Introduction
• GPCR Family Overview
• GPCR Tractability: Current Therapeutics
• GPCR Drug Discovery
• Novel GPCR Features and Impact on Drug Discovery Approaches
• Conclusions

G Protein-Coupled Receptors as Cardiovascular Drug Targets

• Cardiovascular Physiology, Pharmacology, and Therapeutics
• Drugs in Development and Novel Drugs Targets
• Receptor Subtypes as Novel Targets
• Receptor Gene Polymorphisms
• Concluding Remarks

G Protien-Coupled Receptors and Cancer

• Introduction
• Family A GPCRs
• Family C GPCRs
• Frizzled/Smoothened Family of GPCRs
• Virally Encoded GPCRs
• Orphan GPCRs
• Conclusions

G Protein-Coupled Receptors in Metabolic Disease

• Introduction
• Central Mediation of Feeding and Energy Homeostasis
• Peripheral Signals Affecting Nutrient Sensing and Utilization
• Conclusions

G Protien-Coupled Receptors in CNS Drug Discovery

• Introduction
• Psychiatric Diseases
• Pain and Analgesia
• Neurodegeneration
• Neuroendocrine Function
• Orphan GPCRs in the CNS
• Conclusions

Recombinant G Protien-Coupled Receptors for Drug Discovery

• Introduction
• Cell-Free Translation
• E. coli Expression
• Other Prokaryotic Systems
• Yeast Expression
• Insect Cells
• Mammalian Expression
• Comparison of Expression Systems
• Conclusions

High Troughput Screening Assays for G Protein-Coupled Receptors

• Introduction
• Source of Material and Assay Diversity
• High Throughput Screening
• Receptor Binding Assays-General Considerations
• Functional GPCR Assays
• Inverse Agonists and Constitutive Activities
• Microphysiometer Assays
• Screening for Modulators of Orphan Receptors
• Conclusions

Molecular Bioinformatics of Receptor Binding and Activation

• Not All 7TM Receptors are GPCRs
• Receptor Classification by Ligand Size
• Ligand Diversity Conforms to Receptor Phylogeny
• Structural Flexibilities of Membrane Receptors
• Molecular Bioinformatics in Drug Discovery
• Sequence and Structural Searches for an Activation Mechanism
• The Cysteine Shuffle
• Redox Control of Receptor Activation
• Smells Rank as the Smallest 7TMR Agonists
• Bioinformatics with Biological Sense

Structure and Dynamics of G Protein-Coupled Receptors

• Introduction
• Structure, Stability, Dynamics, and Conformational Changes of Rhodopsin
• Structures, Dynamics, and Conformational Changes of GPCRs
• Conclusions

Towards Crystallization of G Protein-Coupled Receptors

• Introduction
• Overexpression and Purification
• Detergent Selection
• Sample Preparation
• Crystallization Methods
• Micelles and Bicelles
• Lipidic Mesophases
• Bicelles, Lipopeptides, and Nanodiscs
• Crystallization
• Case Study: Rhodopsin
• Conclusions

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

• Introduction
• High-Resolution Solid State NMR
• Sample Preparation
• Applications
• Conclusions and Outlook

Structural Genomics Initiatives

• Introduction
• Structural Genomics Programs on Membrane Proteins
• Structural Genomics Initiatives Including GPCRs
• MePNet Approach
• Conclusions

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

• Introduction
• Quarternary Structure of Family A GPCRs
• Consequences of the Dimerization of the Family A GPCRs
• The Mechanisms of Dimerization of the Family A GPCRs
• Conclusions

Orphan Receptors: Promising Targets for Drug Discovery

• Introduction
• Search for Endogenous Ligands of Orphan GPCRs
• Example of Deorphanization: The MCH Systems and Its Impact on Drug Discovery
• Conclusions and Perspectives

Index

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