Structure-Based Drug Discovery,9780854043514

Structure-Based Drug Discovery

by
ISBN13: 9780854043514
ISBN10: 0854043519
Format: Hardcover
Pub. Date: 2006-05-30
Publisher(s): Royal Society of Chemistry
List Price: $195.30

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Summary

The challenge of discovering new medicines has motivated scientists to develop new and innovative technologies and disciplines. Structure-based drug discovery is a collection of methods that exploits the ability to determine and analyse the three-dimensional structure of biological molecules. These methods have been adopted and enhanced to improve the speed and quality of discovery of new drug candidates.

Table of Contents

3D Structure and the Drug Discovery Process
1(31)
Roderick E. Hubbard
Introduction
1(1)
The Drug Discovery Process
2(7)
Establishing a Target
3(2)
Hit Identification
5(1)
Hits to Leads
6(1)
Lead Optimisation
7(1)
Pre-Clinical Trials
8(1)
Clinical Trials
8(1)
Maintaining the Pipeline
9(1)
What is Structure-Based Drug Discovery?
9(4)
From Hype to Application
9(1)
Structural Biology
10(1)
Structure-Based Design
11(1)
Structure-Based Discovery
12(1)
The Evolution of the Ideas of Structure-Based Drug Discovery
13(7)
1960s
13(1)
1970s
14(2)
1980s
16(1)
1990s
17(2)
2000s
19(1)
What isn't in this Book
20(3)
Drug Discovery Against GPCR Targets
20(1)
Protein--Protein Interactions
21(1)
Using Structural Models of ADMET Mechanisms
21(1)
Protein Therapeutics
22(1)
Other Targets for Structure-Based Drug Discovery
22(1)
Concluding Remarks
23(9)
References
24(8)
Structure Determination -- Crystallography for Structure-Based Drug Discovery
32(22)
David G. Brown
Maria M. Flocco
What is X-ray Crystallography?
32(3)
What is Required to Produce a Crystal Structure?
35(1)
Crystallisability of Proteins
36(1)
How does the X-ray Data Relate to the Electron Density? -- The Phase Problem
36(1)
Electron Density Map Interpretation and Atomic Model of the Protein
37(1)
Useful Crystallographic Terminology when Utilising Crystal Structures
38(1)
The Clone-to-Structure Process and SBDD
39(1)
Recent Technological Advances
39(3)
The Role of Crystal Structures in the Discovery Process
42(1)
The Optimal SBDD System
43(1)
Producing a Biologically Relevant Structure
44(1)
Phosphorylation
44(1)
Glycosylation -- Balancing Solubility with Crystallisability
45(1)
Engineering Solubility
46(1)
Specific Crystal Packing Engineering
46(1)
Engineering Stability
47(1)
Use of Surrogate Proteins
47(1)
The Impact of Structural Genomics
48(6)
References
49(5)
Molecular Modelling
54(43)
Xavier Barril
Robert Soliva
Introduction
54(1)
Methods
55(8)
Quantum Chemistry Methods
55(1)
Ligand Internal Energy
56(1)
Study of Reactivity
57(1)
Ligand--Receptor Interaction Energy
57(1)
Parametric Methods
58(1)
Force-Fields
58(1)
Empirical Scoring Functions
59(1)
Statistical Potentials
60(1)
Solvation
60(1)
Sampling Algorithms
61(2)
Applications
63(21)
Target Evaluation
63(1)
Target Druggability
64(3)
Structure Availability and Critical Assessment
67(2)
Hit Finding
69(1)
Docking
69(3)
De novo Design
72(1)
The Role of Chemoinformatics
73(1)
Integrative VS
73(2)
Template or Scaffold Hopping
75(1)
Target Hopping
76(1)
Hit to Lead
77(1)
Binding Mode Determination
77(1)
Improving the Potency of the Hit
78(5)
Modulation of ADMET properties
83(1)
Conclusion
84(13)
References
85(12)
Applications of NMR in Structure-Based Drug Discovery
97(45)
Ben Davis
Julia Hubbard
Introduction
97(1)
The Role of NMR in SBDD
98(1)
Studying Ligand-Receptor Interactions by NMR
98(22)
Detecting Ligand Binding
98(2)
Ligand-Based and Receptor-Based Screening
100(1)
Ligand-Based Approaches
101(1)
Filtered Experiments
101(4)
Magnetization Transfer Experiments
105(7)
Fluorine-Detected Experiments
112(1)
Ligand Displacement by a Known Competitor
113(1)
Receptor-Based Approaches
114(1)
Selective Labeling Strategies
115(1)
Larger Proteins
116(1)
13C labeling
117(1)
Examples of NMR-Screening Approaches
117(1)
Stromelysin
118(1)
Jnk3
119(1)
DNA Gyrase
119(1)
NMR in Structure-Based Lead Optimization
120(11)
Practical Aspects of Ligand--Receptor Complexes
121(1)
Determining Which NMR Approach to Use
121(1)
Methods for Preparation of the Complex
121(1)
NMR Methods for Characterizing Bound Ligands
122(1)
NMR Approaches for Ligand--Receptor Complexes in Fast Exchange
122(5)
NMR Approaches for Ligand/Receptor Complexes in Slow Exchange
127(2)
Chemical-Shift-Based Approaches Combined with Docking
129(2)
Other Applications of NMR in SBDD
131(1)
NMR in Protein Production
131(1)
Protein Structure Determination by NMR
132(1)
Conclusion and Outlook
132(10)
References
134(8)
Fragment Screening: An Introduction
142(31)
Andrew R. Leach
Michael M. Hann
Jeremy N. Burrows
Ed Griffen
Introduction
142(1)
The Concept of Drug-Likeness
142(2)
The Evolution of Lead-Likeness and Fragment Screening
144(10)
Finding Fragments by Screening
154(2)
High Concentration Screening using a Biochemical Assay
155(1)
Biophysical and Direct Structure Determination Screening
155(1)
Screening by Crystallography
155(1)
Screening by Other Biophysical Methods
156(1)
The Design of Fragment Screening Sets
156(5)
Turning Fragment Hits into Leads
161(6)
Fragment Evolution
162(1)
Fragment Linking
163(2)
Fragment Self-Assembly
165(1)
Fragment Optimisation
166(1)
Summary
167(6)
References
169(4)
Iterative Structure-Based Screening of Virtual Chemical' Libraries and Factor Xa: Finding the Orally Available Antithrombotic Candidate LY517717
173(20)
John W. Liebeschuetz
Stuart D. Jones
Michael R. Wiley
Steven C. Young
Introduction
173(2)
Morphology of the Factor Xa Active Site
175(1)
Structure-Based Library Design
176(2)
Design Strategy for Factor Xa
178(4)
Introducing Oral Availability
182(5)
Non-Basic S1 Series
187(1)
Oral Antithrombotic Activity
188(2)
Conclusion
190(3)
Acknowledgements
191(1)
References
191(2)
Anti-Influenza Drugs from Neuraminidase Inhibitors
193(26)
Peter Colman
Introduction
193(1)
Influenza Viruses
193(3)
Early Attempts to Discover Neuraminidase Inhibitors
196(1)
Neuraminidase Structure
196(3)
Structure-Based Discovery of Inhibitors
199(7)
Zanamivir
199(1)
Analogues of Zanamivir
200(3)
Oseltamivir
203(1)
BCX1812 (RWJ270201)
203(2)
A315675
205(1)
Benzoic Acid Frameworks
206(1)
Retrospective Analyses of Inhibitor-Binding
206(1)
Laboratory Studies of Inhibitor Resistant Variants
207(1)
Clinical Studies of Drug Resistance
208(1)
Drug Profiles
209(2)
Pharmacology
209(1)
Efficacy in Therapy
210(1)
Efficacy in Prophylaxis
210(1)
Safety
211(1)
Current Approval Status
211(1)
Conclusions
211(8)
References
212(7)
Isoform Specificity: The Design of Estrogen Receptor-β Selective' Compounds
219(38)
Eric S. Manas
Richard E. Mewshaw
Heather A. Harris
Michael S. Malamas
Introduction
219(3)
Structure-Based Design Methodology
222(7)
Initial Considerations
222(2)
Docking Calculations
224(1)
Quantum Chemical Calculations
225(2)
Interpretation of Structural Information
227(2)
The Design of Aryl Diphenolic Azoles As ERβ Selective Agonists
229(7)
Phenyl and Naphthyl Isoxazoles
229(3)
Phenyl and Naphthyl Benzoxazoles
232(4)
Learning From and Moving Beyond the Genistein Scaffold
236(9)
Biphenyl Scaffolds
236(2)
Phenyl Napthalenes
238(6)
Constrained Phenyl-Naphthalene Analogs: Dibenzochromenes
244(1)
Evaluation of ERβ Selective Compounds in Biological Assays
245(4)
Conclusions
249(8)
Acknowledgments
250(1)
References
250(7)
Subject Index 257

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