GPCR Molecular Pharmacology and Drug Targeting

G protein-coupled receptors (GPCRs) are a large protein family of transmembrane receptors vital in dictating cellular responses. GPCRs are involved in many diseases, but are also the target of around half of all modern medicinal drugs. Shifting Paradigms in G Protein Coupled Receptors takes a look at the way GPCRs are examined today, how they react, how their mutations lead to disease, and the many ways in which they can be screened for compounds that modulate them. Chemists, pharmacologists, and biologists will find essential information in this comprehensive reference.

Auteur
Annette Gilchrist, PhD, is Assistant Professor of Pharmaceutical Sciences at Midwestern Univeristy's Chicago of Pharmacy, and Adjunct Professor at Northwestern University in the Department of Molecular Pharmacology and Biological Chemistry. Previously, she cofounded and was chief scientific officer for Caden Biosciences, and cofounded and was president of Cue BIOtech, companies committed to GPCR discovery efforts. A life sciences industry consultant and regular speaker at ACS, SBS, DIA, BIO, and CHI conferences, she has twenty-four peer-reviewed publications and four issued patents.

Texte du rabat
The fundamental guide on the basic concepts and medical significance of GPCRs The focus of this book, G protein-coupled receptors (GPCRs) are a large protein family of transmembrane proteins that sense molecules outside the cell and relay the information, thus initiating cellular responses. When this molecular process breaks down, GPCRs become the culprit of many diseases, making them the target of nearly half of all modern medicinal drugs.

GPCR Molecular Pharmacology and Drug Targeting examines the complex inner workings of these proteins by balancing basic research concepts with practical aspects relevant to drug discovery. Throughout, it answers key questions surrounding research into GPCR functionhow they get activated; how they signal across the cell membrane; how they couple to intracellular signaling partners; how they communicate to each other as well as to other receptors and other membrane proteins; and how their mutations lead to disease. At the same time, it explores the many ways in which the receptors can be screened at each of these critical steps for compounds that modulate their action. This book:

• Details major developments in the field of GPCR research and applications, including recent progress in crystallography and label-free screening approaches

• Provides vital information for scientists working to identify compounds that selectively target GPCRs

• Covers key topics including structure-based drug design, deorphanization, dimerization, functional selectivity, and accessory proteins

• Presents detailed methods on how to express and manipulate GPCRs, as well as established and emerging methods to measure their activity

GPCR Molecular Pharmacology and Drug Targeting provides the historical groundwork and acts as an essential resource for any scientists working with this important and therapeutically relevant family. The in-depth discussions on recent findings and extensive coverage of screening approaches provide the necessary framework for encouraging exploration into malfunctioning GPCRs and identifying novel medicinal solutions.

Contenu
Preface. Contributors.

1. The Evolution of Receptors: From OnOff Switches to Microprocessors (Terry Kenakin).

1.1. Introduction.

1.2. The Receptor as an OnOff Switch.

1.3. Historical Background and Classical Receptor Theory.

1.4. The Operational Model of Drug Action.

1.5. Receptor Antagonism.

1.6. Specific Models of GPCRs (7TM Receptors).

1.7. The Receptor as Microprocessor: Ternary Complex Models.

1.8. Receptors as Basic Drug Recognition Units.

1.9. Receptor Structure.

1.10. Future Considerations.

References.

2. The Evolving Pharmacology of GPCRs 27 (Lauren T. May, Nicholas D. Holliday, and Stephen J. Hill).

2.1. Agonists, Neutral Antagonists, and Inverse Agonists.

2.2. LDTRS/Protean Agonism.

2.3. Molecular Mechanisms of GPCR Ligand Binding.

2.4. Two GPCR Ligands Binding at OnceConcept of Allosterism.

2.5. GPCR Dimerization.

2.6. Future Perspectives.

Acknowledgments.

References.

3. The Emergence of Allosteric Modulators for G Protein-Coupled Receptors (Karen J. Gregory, Celine Valant, John Simms, Patrick M. Sexton, and Arthur Christopoulos).

3.1. Introduction.

3.2. Foundations of Allosteric Receptor Theory.

3.3. Models for Understanding the Effects of Allosteric Modulators.

3.4. Types of Allosteric Modulators and Their Properties.

3.5. Detection and Quantification of Allosteric Interactions.

3.6. Some Examples of GPCR Allosteric Modulators.

3.7. Concluding Remarks.

References.

4. Receptor-Mediated G Protein Activation: How, How Many, and Where? (Ingrid Gsandtner, Christian W. Gruber, and Michael Freissmuth).

4.1. The Mechanical ProblemThree Different Solutions.

4.2. Receptor MonomersDimersOligomers: One Size Fits All?

4.3. Corrals, Fences, RaftsAre There Privileged Places for GPCR Activation?

Acknowledgments.

References.

5. Molecular Pharmacology of Frizzledswith Implications for Possible Therapy (Gunnar Schulte).

5.1. Introduction.

5.2. Frizzleds as WNT Receptors.

5.3. Frizzled Signaling 120.

5.4. FrizzledsPhysiology and Possible Therapy.

Acknowledgments.

References.

6. Secretin Receptor Dimerization: A Possible Functionally Important Paradigm for Family B G Protein-Coupled Receptors (Kaleeckal G. Harikumar, Maoqing Dong, and Laurence J. Miller).

6.1. Methodological Approaches to GPCR Oligomerization.

6.2. Structural Themes for GPCR Oligomerization.

6.3. Functional Effects of GPCR Oligomerization.

6.4. Secretin Receptor Oligomerization.

References.

7. Past and Future Strategies for GPCR Deorphanization (Angélique Levoye, Nathalie Clement, Elodie Tenconi and Ralf Jockers).

7.1. Introduction.

7.2. Current Strategies to Identify the Ligand and Function of Orphan 7TM Proteins.

7.3. Functional Assays for Deorphanization.

7.4. Future Directions and New Concepts.

7.5. Controversial Issues.

Acknowledgments.

References.

8. High-Throughput GPCR Screening Technologies and the Emerging Importance of the Cell Phenotype (Terry Reisine and Richard M. Eglen).

8.1. Introduction.

8.2. How Are GPCR Drugs Discovered?

8.3. GPCR Dependence on G Proteins.

8.4. Technologies for GPCR Compound Screening and Drug Discovery.

8.5. Importance of Target Cells in GPCR HTS Assays.

8.6. Summary.

References. **9. Are "Traditional" Biochemical Techniques Out of Fashion in the New Era of GPCR Pharma...