Structure-Based Drug Discovery

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ISBN: 9780854043514 | 0854043519
Cover: Hardcover
Copyright: 5/30/2006

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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.

3D Structure and the Drug Discovery Process

(31)

Roderick E. Hubbard

Introduction

(1)

The Drug Discovery Process

(7)

Establishing a Target

(2)

Hit Identification

(1)

Hits to Leads

(1)

Lead Optimisation

(1)

Pre-Clinical Trials

(1)

Clinical Trials

(1)

Maintaining the Pipeline

(1)

What is Structure-Based Drug Discovery?

(4)

From Hype to Application

(1)

Structural Biology

(1)

Structure-Based Design

(1)

Structure-Based Discovery

(1)

The Evolution of the Ideas of Structure-Based Drug Discovery

(7)

1960s

(1)

1970s

(2)

1980s

(1)

1990s

(2)

2000s

(1)

What isn't in this Book

(3)

Drug Discovery Against GPCR Targets

(1)

Protein--Protein Interactions

(1)

Using Structural Models of ADMET Mechanisms

(1)

Protein Therapeutics

(1)

Other Targets for Structure-Based Drug Discovery

(1)

Concluding Remarks

(9)

References

(8)

Structure Determination -- Crystallography for Structure-Based Drug Discovery

(22)

David G. Brown

Maria M. Flocco

What is X-ray Crystallography?

(3)

What is Required to Produce a Crystal Structure?

(1)

Crystallisability of Proteins

(1)

How does the X-ray Data Relate to the Electron Density? -- The Phase Problem

(1)

Electron Density Map Interpretation and Atomic Model of the Protein

(1)

Useful Crystallographic Terminology when Utilising Crystal Structures

(1)

The Clone-to-Structure Process and SBDD

(1)

Recent Technological Advances

(3)

The Role of Crystal Structures in the Discovery Process

(1)

The Optimal SBDD System

(1)

Producing a Biologically Relevant Structure

(1)

Phosphorylation

(1)

Glycosylation -- Balancing Solubility with Crystallisability

(1)

Engineering Solubility

(1)

Specific Crystal Packing Engineering

(1)

Engineering Stability

(1)

Use of Surrogate Proteins

(1)

The Impact of Structural Genomics

(6)

References

(5)

Molecular Modelling

(43)

Xavier Barril

Robert Soliva

Introduction

(1)

Methods

(8)

Quantum Chemistry Methods

(1)

Ligand Internal Energy

(1)

Study of Reactivity

(1)

Ligand--Receptor Interaction Energy

(1)

Parametric Methods

(1)

Force-Fields

(1)

Empirical Scoring Functions

(1)

Statistical Potentials

(1)

Solvation

(1)

Sampling Algorithms

(2)

Applications

(21)

Target Evaluation

(1)

Target Druggability

(3)

Structure Availability and Critical Assessment

(2)

Hit Finding

(1)

Docking

(3)

De novo Design

(1)

The Role of Chemoinformatics

(1)

Integrative VS

(2)

Template or Scaffold Hopping

(1)

Target Hopping

(1)

Hit to Lead

(1)

Binding Mode Determination

(1)

Improving the Potency of the Hit

(5)

Modulation of ADMET properties

(1)

Conclusion

(13)

References

(12)

Applications of NMR in Structure-Based Drug Discovery

(45)

Ben Davis

Julia Hubbard

Introduction

(1)

The Role of NMR in SBDD

(1)

Studying Ligand-Receptor Interactions by NMR

(22)

Detecting Ligand Binding

(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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Structure-Based Drug Discovery

Summary

Table of Contents

Supplemental Materials