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E-grāmata: Ligand Design for G Protein-coupled Receptors

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Contributors identified only by name offer clues to drug designers on designing ligands that will target G protein-coupled receptors, which comprise over 60% of all that receptors, and so should not be all that hard to hit. They emphasize fundamental and methodological issues, and consider the entire protein family at a genomic level. Among their topics are the receptors in the human genome, a novel drug screening assay, molecular mechanisms of receptor activation, chemogenomic approaches, and the three-dimensional structure of the receptors. Annotation ©2006 Book News, Inc., Portland, OR (booknews.com)

G protein-coupled receptors (GPCRs) are one of the most important target classes in pharmacology and are the target of many blockbuster drugs. Yet only with the recent elucidation of the rhodopsin structure have these receptors become amenable to a rational drug design.

Based on recent examples from academia and the pharmaceutical industry, this book demonstrates how to apply the whole range of bioinformatics, chemoinformatics and molecular modeling tools to the rational design of novel drugs targeting GPCRs.

Essential reading for medicinal chemists and drug designers working with this largest class of drug targets in the human genome.

Preface xiii
G Protein-coupled Receptors in the Human Genome
1(26)
Robert Fredriksson
Helgi B. Schioth
Introduction
1(1)
The Adhesion Family
2(3)
The Secretin Family
5(1)
The Frizzled/Taste 2 Family
5(3)
The Frizzled Receptor Cluster
6(2)
The Taste 2 Receptor Cluster
8(1)
The Glutamate Family
8(3)
The Rhodopsin Family
11(4)
The Rhodopsin α-Group
11(1)
The Prostaglandin Receptor Cluster
11(1)
The Amine Receptor Cluster
12(1)
The Opsin Receptor Cluster
13(1)
The Melatonin Receptor Cluster
14(1)
The MECA Receptor Cluster
14(1)
Other Rhodopsin α-Receptors
14(1)
Rhodopsin β-Group
15(1)
Rhodopsin γ-Group
15(3)
The SOG Receptor Cluster
16(1)
The Melanocyte Concentrating Hormone Receptor Cluster
17(1)
The Chemokine Receptor Cluster
18(1)
Other Rhodopsin γ-Receptors
18(1)
The Rhodopsin δ-Group
18(3)
The MAS-related Receptor Cluster
18(2)
The Glycoprotein Receptor Cluster
20(1)
The Coagulation Factor Receptor Cluster
20(1)
The Purinergic Receptor Cluster
20(1)
The Olfactory Receptor Cluster
20(1)
Other Rhodopsin α-Receptors
20(1)
Other GPCRs
21(1)
Future Perspective
21(6)
References
23(4)
Why G Protein-coupled Receptors Databases are Needed
27(24)
Jacques Haiech
Jean-Luc Galzi
Marie-Claude Kilhoffer
Marcel Hibert
Didier Rognan
Introduction
27(1)
A Non-exhaustive List of the GPCR Data Models
27(1)
Using the Central Dogma of Biology
28(2)
Using the Tree of Life
30(5)
Using a Chemogenomic Approach
35(3)
Conclusion
38(13)
References
38(13)
A Novel Drug Screening Assay for G Protein-coupled Receptors
51(10)
Brian F. O'Dowd
Xiaodong Ji
Mohammad Alijaniaram
Tuan Nguyen
Susan R. George
Introduction
51(2)
History
51(1)
Nuclear Translocation of Endogenous GPCRs
52(1)
The MOCA Method
52(1)
The MOCA Strategy Demonstrated with the D1 Dopamine Receptor
53(3)
Development of the Assay
53(2)
Concentration-dependent Antagonist Blockade of Nuclear Transport
55(1)
Measurement of Receptor Cell Surface Expression: Antagonist Binding of Receptors at Cell Surface
55(1)
Development of Quantitative Methodology Suitable for High Throughput Analysis
56(2)
Nuclear Translocation of Orphan GPCRs
58(1)
Discussion of the MOCA Method
58(1)
Conclusion
59(2)
References
60(1)
Importance of GPCR Dimerization for Function: The Case of the Class C GPCRs
61(22)
Laurent Prezeau
Cyril Goudet
Philippe Rondard
Jean-Philippe Pin
Introduction
61(1)
Class C GPCRs are Multidomain Proteins
62(4)
The VFT
63(1)
The CRD
64(1)
The HD
65(1)
C-Tail
66(1)
Class C GPCRs are Constitutive Dimers
66(1)
Agonists Activate Class C GPCRs by Stabilizing the Closed State of the VFT
67(1)
Dimeric Functioning of the Dimer of VFTs
68(3)
Agonist Stoichiometry: Symmetry or Asymmetry?
70(1)
The Heptahelical Domain, the Target of Positive and Negative Allosteric Modulators, Behaves in a Manner Similar to Rhodopsin-like Class A GPCRs
71(2)
Allosteric Coupling Between the Extracellular and Heptahelical Domains within the Dimer
73(2)
Molecular Determinants of the Coupling Between the VFT and the HD
73(1)
Cis- and Trans-activation Can Exist within Class C GPCRs
74(1)
Asymmetric Functioning of the HD Dimer
75(1)
Conclusion
76(7)
References
77(6)
Molecular Mechanisms of GPCR Activation
83(16)
Robert P. Bywater
Paul Denny-Gouldson
Structure of G Protein-coupled Receptors
83(1)
Activation of GPCRs by Endogenous Ligands: The Concept of Receptor Agonism
84(1)
Distinction Between Orthosteric and Allosteric Ligands
84(1)
Only a Few Receptor Types are Known to Possess an Endogenous Antagonist
85(1)
Constitutively Active GPCRs
86(1)
Mechanism of GPCR Activation: The Active/Inactive ``Switch''
86(2)
GPCR Dimerization
88(1)
Activation of G Proteins
89(1)
Interaction Between GPCRs and G Proteins
90(1)
Conclusions
91(8)
References
92(7)
Allosteric Properties and Regulation of G Protein-coupled Receptors
99(16)
Jean-Luc Galzi
Emeline Maillet
Sandra Lecat
Muriel Hachet-Haas
Jacques Haiech
Marcel Hibert
Brigitte Ilien
Introduction
99(2)
Multiple Conformations and Signaling Pathways of G Protein-coupled Receptors
101(4)
Biophysical Approaches to Monitoring Conformational Changes of G Protein-coupled Receptors
102(3)
Allosteric Modulators of G Protein-coupled Receptors
105(2)
Where Do Allosteric Modulators Bind on GPCRs?
107(4)
Future Challenges for Allosteric Modulation of GPCRs
111(4)
References
112(3)
Chemogenomics Approaches to Ligand Design
115(22)
Thomas Klabunde
Introduction to Chemogenomics: Similar Receptors Bind Similar Ligands
115(2)
Focused Libraries and Screening Collections Directed Against GPCRs
117(7)
Physicochemical Property-based Selection of GPCR Screening Sets
118(1)
Pharmacophore and Molecular Descriptors for GPCR Directed Libraries
118(2)
Privileged-fragment-based GPCR-directed Libraries
120(1)
GPCR Collection and Subfamily-directed Library Design
121(3)
Understanding Molecular Recognition: Impact on GPCR Ligand Design
124(8)
Sites for Ligand Recognition within Biogenic-amine-binding and Other GPCRs
125(2)
Design of GPCR-directed Libraries Using ``Motifs'' and ``Themes''
127(1)
``Chemoprints'' for Recognition of GPCR-privileged Fragments
127(4)
Molecular Interaction Models by Proteochemometrics
131(1)
Outlook
132(5)
References
133(4)
Strategies for the Design of pGPCR-targeted Libraries
137(28)
Nikolay P. Savchuk
Sergey E. Tkachenko
Konstantin V. Balakin
Introduction
137(4)
Peptidergic GPCRs: Brief Overview
137(3)
Endogenous Ligands for pGPCRs
140(1)
Potential Therapeutic Targets of pGPCRs
140(1)
Approaches to the Design of pGPCR-targeted Libraries
141(15)
Problems in Drug Discovery Directed Towards pGPCRs
143(3)
Docking and Pharmacophore-based Design
146(2)
Knowledge-based Data Mining Approaches
148(1)
Chemogenomics Approaches
149(1)
Incorporation of Specific Biomolecular Recognition Motifs
149(1)
Privileged Structures
150(4)
Mimetics of the Peptide Secondary Structure Elements
154(2)
Synthesis of pGPCR-focused Libraries: Example of a Practical Methodology
156(3)
Conclusions
159(6)
References
160(5)
Ligand-based Rational Design: Virtual Screening
165(18)
David E. Clark
Christopher Higgs
Introduction
165(1)
Why Use Ligand-based Virtual Screening?
166(1)
Speed
166(1)
Applicability
166(1)
Complementarity
166(1)
Overview of Ligand-based Virtual Screening
167(3)
Starting Points
167(1)
Chemical Structure Databases
167(1)
Database Search Techniques
168(1)
2-D Substructure Searching
168(1)
2-D Similarity Searching
169(1)
3-D Substructure Searching
170(1)
3-D Similarity Searching
170(1)
Pharmacophore Searching
170(1)
Successful Applications of Ligand-based Virtual Screening for GPCRs
170(9)
Somatostatin Agonists
171(1)
Muscarinic M3 Receptor Antagonists
172(2)
Urotensin II Antagonists
174(2)
Melanin-concentrating Hormone-1 Receptor Antagonists
176(2)
Growth Hormone Secretagogue Receptor Agonists
178(1)
Conclusions
179(4)
References
180(3)
3-D Structure of G Protein-coupled Receptors
183(22)
Leonardo Pardo
Xavier Deupi
Cedric Govaerts
Mercedes Campillo
Introduction
183(2)
Classification of G Protein-coupled Receptors
185(1)
The Extracellular N-terminal Domain of G Protein-coupled Receptors
185(1)
Sequence Analyses of the 7TM Segments of the Rhodopsin Family of G Protein-coupled Receptors
185(1)
The Conformation of Pro-kinked Transmembrane α-Helices
186(1)
Helix Deformation in the Rhodopsin Family of G Protein-coupled Receptors
187(6)
Transmembrane Helix 1
187(1)
Transmembrane Helix 2
188(2)
Transmembrane Helix 3
190(1)
Transmembrane Helix 4
190(1)
Transmembrane Helix 5
190(2)
Transmembrane Helix 6
192(1)
Transmembrane Helix 7
193(1)
Structural and Functional Role of Internal Water Molecules
193(2)
A Conserved Hydrogen Bond Network Linking D2.50 and W6.48
194(1)
The Environment of the NPxxY Motif in TM7
195(1)
Molecular Processes of Receptor Activation
195(3)
Molecular Processes Initiated by the Recognition of the Extracellular Ligand by the Receptor
196(1)
Molecular Processes that Propagate the Signal from the Ligand Binding Site to the Intracellular Amino Acids of the Transmembrane Bundle
196(2)
Conclusions
198(7)
References
199(6)
7TM Models in Structure-based Drug Design
205(36)
Frank E. Blaney
Anna-Maria Capelli
Giovanna Tedesco
Introduction
205(2)
Early Models of 7TM Receptors
207(1)
Third Generation 7TM Models
208(6)
Docking Ligands into Receptor Models
209(1)
Designing 5-HT2C Selective Antagonists
210(2)
Even Wrong Models Can be Useful: The Importance of SDM Studies
212(2)
Fourth Generation Models
214(1)
Revisiting the 5-HT2c Antagonist Binding Site
214(1)
The Inclusion of Extracellular Loops in 7TM Models
215(3)
Switching Selectivity in Neurokinin Antagonists
218(5)
Homology (Fifth Generation) Models of 7TM Receptors
223(1)
``Ligand-based'' Design of 7TM Receptor Compounds
223(5)
Pharmacophores Often do NOT Work
226(2)
Refinement of 7TM Pharmacophores Using Current Receptor Models
228(2)
Optimizing Properties of the CCR2 Antagonists
230(3)
Some General Ligand Considerations When Docking
233(3)
What the Future Holds
236(1)
Abbreviations and Nomenclature
236(5)
References
237(4)
Receptor-based Rational Design: Virtual Screening
241(20)
Didier Rognan
Introduction
241(1)
Structure-based Screening Workflow
242(5)
Setting Up a Ligand Library
242(2)
Docking and Scoring
244(2)
Data Post-processing
246(1)
Retrospective Screening
247(3)
Give it a Try
247(2)
Several Alternative Screening Strategies
249(1)
Prospective Screening
250(5)
Screening Rhodopsin-based Ligand-biased Homology Models
250(3)
Screening Ab Initio Models
253(1)
A Few Difficult Screening Scenarios
253(2)
Conclusions
255(6)
References
256(5)
Subject Index 261
Didier Rognan leads the Drug Bioinformatics Group at the Laboratory for Molecular Pharmacochemistry in Illkirch (France). He obtained a graduate degree in Pharmacy from the University of Rennes and completed his PhD in Medicinal Chemistry at the University of Strasbourg under the supervision of Camille G. Wermuth in 1989. Moving to the Swiss Federal Institute of Technology in Z?he became Assistant Professor at the ETH before being named a research director at the CRNS in Illkirch near Strasbourg in 2000. Professor Rognan is mainly interested in all aspects (method development, applications) of protein-based drug design and virtual screening.
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