Fragment-based Approaches in Drug Discovery

, by Jahnke, Wolfgang; Erlanson, Daniel A.; Mannhold, Raimund; Kubinyi, Hugo; Folkers, Gerd

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ISBN: 9783527312917 | 3527312919
Cover: Hardcover
Copyright: 9/11/2006

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Recent successes in the modular design of pharmacologically active ligands show how the concept of fragment-based ligand design is quickly pervading research departments throughout the drug industry. Fragment-based ligand design combines high-throughput screening with structure-based design to form a powerful new tool in drug discovery.

Preface

A Personal Foreword

XVII

List of Contributors

XIX

Part I: Concept and Theory

1 The Concept of Fragment-based Drug Discovery

(8)

Daniel A. Erlanson and Wolfgang Jahnke

1.1 Introduction

(1)

1.2 Starting Small: Key Features of Fragment-based Ligand Design

(2)

1.2.1 FBS Samples Higher Chemical Diversity

(1)

1.2.2 FBS Leads to Higher Hit Rates

(1)

1.2.3 FBS Leads to Higher Ligand Efficiency

(1)

1.3 Historical Development

(1)

1.4 Scope and Overview of this Book

(2)

References

(2)

2 Multivalency in Ligand Design

(44)

Vijay M. Krishnamurthy, Lora A. Estroff and George M. Whitesides

2.1 Introduction and Overview

(1)

2.2 Definitions of Terms

(4)

2.3 Selection of Key Experimental Studies

(3)

2.3.1 Trivalency in a Structurally Simple System

(1)

2.3.2 Cooperativity (and the Role of Enthalpy) in the "Chelate Effect"

(1)

2.3.3 Oligovalency in the Design of Inhibitors to Toxins

(1)

2.3.4 Bivalency at Well Defined Surfaces (Self-assembled Monolayers, SAMs)

(1)

2.3.5 Polyvalency at Surfaces of Viruses, Bacteria, and SAMs

(1)

2.4 Theoretical Considerations in Multivalency

(7)

2.4.1 Survey of Thermodynamics

(1)

2.4.2 Additivity and Multivalency

(3)

2.4.3 Avidity and Effective Concentration (Ceff)

(2)

2.4.4 Cooperativity is Distinct from Multivalency

(1)

2.4.5 Conformational Entropy of the Linker between Ligands

(1)

2.4.6 Enthalpy/Entropy Compensation Reduces the Benefit of Multivalency

(1)

2.5 Representative Experimental Studies

(6)

2.5.1 Experimental Techniques Used to Examine Multivalent Systems

(1)

2.5.1.1 Isothermal Titration Calorimetry

(1)

2.5.1.2 Surface Plasmon Resonance Spectroscopy

(1)

2.5.1.3 Surface Assays Using Purified Components (Cell-free Assays)

(1)

2.5.1.4 Cell-based Surface Assays

(1)

2.5.2 Examination of Experimental Studies in the Context of Theory

(1)

2.5.2.1 Trivalency in Structurally Simple Systems

(1)

2.5.2.2 Cooperativity (and the Role of Enthalpy) in the "Chelate Effect"

(1)

2.5.2.3 Oligovalency in the Design of Inhibitors of Toxins

(1)

2.5.2.4 Bivalency in Solution and at Well Defined Surfaces (SAMs)

(1)

2.5.2.5 Polyvalency at Surfaces (Viruses, Bacteria, and SAMs)

(1)

2.6 Design Rules for Multivalent Ligands

(7)

2.6.1 When Will Multivalency Be a Successful Strategy to Design Tight-binding Ligands?

(1)

2.6.2 Choice of Scaffold for Multivalent Ligands

(1)

2.6.2.1 Scaffolds for Oligovalent Ligands

(1)

2.6.2.2 Scaffolds for Polyvalent Ligands

(1)

2.6.3 Choice of Linker for Multivalent Ligands

(1)

2.6.3.1 Rigid Linkers Represent a Simple Approach to Optimize Affinity

(1)

2.6.3.2 Flexible Linkers Represent an Alternative Approach to Rigid Linkers to Optimize Affinity

(1)

2.6.4 Strategy for the Synthesis of Multivalent Ligands

(1)

2.6.4.1 Polyvalent Ligands: Polymerization of Ligand Monomers

(1)

2.6.4.2 Polyvalent Ligands: Functionalization with Ligands after Polymerization

(1)

2.7 Extensions of Multivalency to Lead Discovery

(5)

2.7.1 Hetero-oligovalency Is a Broadly Applicable Concept in Ligand Design

(1)

2.7.2 Dendrimers Present Opportunities for Multivalent Presentation of Ligands

(1)

2.7.3 Bivalency in the Immune System

(2)

2.7.4 Polymers Could Be the Most Broadly Applicable Multivalent Ligands

(2)

2.8 Challenges and Unsolved Problems in Multivalency

(1)

2.9 Conclusions

(1)

Acknowledgments

(1)

References

(10)

3 Entropic Consequences of Linking Ligands

(12)

Christopher W. Murray and Marcel L. Verdonk

3.1 Introduction

(1)

3.2 Rigid Body Barrier to Binding

(2)

3.2.1 Decomposition of Free Energy of Binding

(1)

3.2.2 Theoretical Treatment of the Rigid Body Barrier to Binding

(1)

3.3 Theoretical Treatment of Fragment Linking

(2)

3.4 Experimental Examples of Fragment Linking Suitable for Analysis

(2)

3.5 Estimate of Rigid Body Barrier to Binding

(1)

3.6 Discussion

(2)

3.7 Conclusions

(1)

References

(2)

4 Location of Binding Sites on Proteins by the Multiple Solvent Crystal Structure Method

(24)

Dagmar Ringe and Carla Mattos

4.1 Introduction

(1)

4.2 Solvent Mapping

(1)

4.3 Characterization of Protein–Ligand Binding Sites

(2)

4.4 Functional Characterization of Proteins

(1)

4.5 Experimental Methods for Locating the Binding Sites of Organic Probe Molecules

(1)

4.6 Structures of Elastase in Nonaqueous Solvents

(1)

4.7 Organic Solvent Binding Sites

(2)

4.8 Other Solvent Mapping Experiments

(3)

4.9 Binding of Water Molecules to the Surface of a Protein

(1)

4.10 Internal Waters

(1)

4.11 Surface Waters

(1)

4.12 Conservation of Water Binding Sites

(1)

4.13 General Properties of Solvent and Water Molecules on the Protein

(1)

4.14 Computational Methods

(2)

4.15 Conclusion

(1)

Acknowledgments

(1)

References

(6)

Part 2: Fragment Library Design and Computional Approaches

5 Cheminformatics Approaches to Fragment-based Lead Discovery

(22)

Tudor I. Oprea and Jeffrey M. Blaney

5.1 Introduction

(1)

5.2 The Chemical Space of Small Molecules (Under 300 a.m.u.)

(2)

5.3 The Concept of Lead-likeness

(2)

5.4 The Fragment-based Approach in Lead Discovery

(3)

5.5 Literature-based Identification of Fragments: A Practical Example

(8)

5.6 Conclusions

107

(2)

Acknowledgments

109

(1)

References

109

(4)

6 Structural Fragments in Marketed Oral Drugs

113

(12)

Michal Vieth and Miles Siegel

6.1 Introduction

113

(1)

6.2 Historical Look at the Analysis of Structural Fragments of Drugs

113

(2)

6.3 Methodology Used in this Analysis

115

(3)

6.4 Analysis of Similarities of Different Drug Data Sets Based on the Fragment Frequencies

118

(5)

6.5 Conclusions

123

(1)

Acknowledgments

124

(1)

References

124

(1)

7 Fragment Docking to Proteins with the Multi-copy Simultaneous Search Methodology

125

(24)

Collin M. Stultz and Martin Karplus

7.1 Introduction

125

(1)

7.2 The MCSS Method

125

(7)

7.2.1 MCSS Minimizations

126

(1)

7.2.2 Choice of Functional Groups

126

(1)

7.2.3 Evaluating MCSS Minima

127

(5)

7.3 MCSS in Practice: Functionality Maps of Endothiapepsin

132

(3)

7.4 Comparison with GRID

135

(2)

7.5 Comparison with Experiment

137

(1)

7.6 Ligand Design with MCSS

138

(3)

7.6.1 Designing Peptide-based Ligands to Ras

138

(2)

7.6.2 Designing Non-peptide Based Ligands to Cytochrome P450

140

(1)

7.6.3 Designing Targeted Libraries with MCSS

140

(1)

7.7 Protein Flexibility and MCSS

141

(2)

7.8 Conclusion

143

(1)

Acknowledgments

144

(1)

References

144

(5)

Part 3: Experimental Techniques and Applications

8 NMR-guided Fragment Assembly

149

(32)

Daniel S. Sem

8.1 Historical Developments Leading to NM R-based Fragment Assembly

149

(1)

8.2 Theoretical Foundation for the Linking Effect

150

(2)

8.3 NMR-based Identification of Fragments that Bind Proteins

152

(11)

8.3.1 Fragment Library Design Considerations

152

(2)

8.3.2 The "SHAPES" NMR Fragment Library

154

(2)

8.3.3 The "SAR by NMR" Fragment Library

156

(4)

8.3.4 Fragment-based Classification of protein Targets

160

(3)

8.4 NMR-based Screening for Fragment Binding

163

(4)

8.4.1 Ligand-based Methods

163

(2)

8.4.2 Protein-based Methods

165

(2)

8.4.3 High-throughput Screening: Traditional and TINS

167

(1)

8.5 NMR-guided Fragment Assembly

167

(4)

8.5.1 SAR by NMR

167

(2)

8.5.2 SHAPES

169

(1)

8.5.3 Second-site Binding Using Paramagnetic Probes

169

(1)

8.5.4 NMR-based Docking

170

(1)

8.6 Combinatorial NMR-based Fragment Assembly

171

(5)

8.6.1 NMR SOLVE

171

(2)

8.6.2 NMR ACE

173

(3)

8.7 Summary and Future Prospects

176

(1)

References

177

(4)

9 SAR by NMR: An Analysis of Potency Gains Realized Through Fragment-linking and Fragment-elaboration Strategies for Lead Generation

181

(12)

Philip J. Hajduk, Jeffrey R. Huth, and Chaohong Sun

9.1 Introduction

181

(1)

9.2 SAR by NMR

182

(1)

9.3 Energetic Analysis of Fragment Linking Strategies

183

(4)

9.4 Fragment Elaboration

187

(1)

9.5 Energetic Analysis of Fragment Elaboration Strategies

188

(2)

9.6 Summary

190

(1)

References

191

(2)

10 Pyramid: An Integrated Platform for Fragment-based Drug Discovery

193

(1)

Thomas G. Davies, Rob L.M. van Montfort, Glyn Williams, and Harren Jhoti

10.1 Introduction

193

(1)

10.2 The Pyramid Process

194

(13)

10.2.1 Introduction

194

(1)

10.2.2 Fragment Libraries

195

(1)

10.2.2.1 Overview

195

(1)

10.2.2.2 Physico-chemical Properties of Library Members

196

(1)

10.2.2.3 Drug Fragment Library

197

(1)

10.2.2.4 Privileged Fragment Library

197

(1)

10.2.2.5 Targeted Libraries and Virtual Screening

197

(1)

10.2.2.6 Quality Control of Libraries

201

(1)

10.2.3 Fragment Screening

201

(1)

10.2.4 X-ray Data Collection

202

(1)

10.2.5 Automation of Data Processing

203

(2)

10.2.6 Hits and Diversity of Interactions

205

(1)

10.2.6.1 Example 1: Compound 1 Binding to CDK2

205

(1)

10.2.6.2 Example 2: Compound 2 Binding to p38a

207

(1)

10.2.6.3 Example 3: Compound 3 Binding to Thrombin

207

(1)

10.3 Pyramid Evolution – Integration of Crystallography and NMR

207

(4)

10.3.1 NMR Screening Using Water-LOGSY

208

(2)

10.3.2 Complementarity of X-ray and NMR Screening

210

(1)

10.4 Conclusions

211

(1)

Acknowledgments

211

(1)

References

212

(3)

11 Fragment-based Lead Discovery and Optimization Using X-Ray Crystallography, Computational Chemistry, and High-throughput Organic Synthesis

215

(1)

Jeff Blaney, Vicki Nienaber, and Stephen K. Burley

11.1 Introduction

215

(2)

11.2 Overview of the SGX Structure-driven Fragment-based Lead Discovery Process

217

(1)

11.3 Fragment Library Design for Crystallographic Screening

218

(3)

11.3.1 Considerations for Selecting Fragments

218

(1)

11.3.2 SGX Fragment Screening Library Selection Criteria

219

(1)

11.3.3 SGX Fragment Screening Library Properties

220

(1)

11.3.4 SGX Fragment Screening Library Diversity: Theoretical and Experimental Analyses

220

(1)

11.4 Crystallographic Screening of the SGX Fragment Library

221

(9)

11.4.1 Overview of Crystallographic Screening

222

(2)

11.4.2 Obtaining the Initial Target Protein Structure

224

(1)

11.4.3 Enabling Targets for Crystallographic Screening

225

(1)

11.4.4 Fragment Library Screening at SGX-CAT

225

(1)

11.4.5 Analysis of Fragment Screening Results

226

(2)

11.4.6 Factor VIIa Case Study of SGX Fragment Library Screening

228

(2)

11.5 Complementary Biochemical Screening of the SGX Fragment Library

230

(2)

11.6 Importance of Combining Crystallographic and Biochemical Fragment Screening

232

(1)

11.7 Selecting Fragments Hits for Chemical Elaboration

233

(1)

11.8 Fragment Optimization

234

(9)

11.8.1 Spleen Tyrosine Kinase Case Study

234

(6)

11.8.2 Fragment Optimization Overview

240

(1)

11.8.3 Linear Library Optimization

241

(1)

11.8.4 Combinatorial Library Optimization

242

(1)

11.9 Discussion and Conclusions

243

(2)

11.10 Postscript: SGX Oncology Lead Generation Program

245

(1)

References

245

(4)

12 Synergistic Use of Protein Crystallography and Solution-phase NMR Spectroscopy in Structure-based Drug Design: Strategies and Tactics

249

(1)

Cele Abad-Zapatero, Geoffrey F. Stamper, and Vincent S. Stoll

12.1 Introduction

249

(3)

12.2 Case 1: Human Protein Tyrosine Phosphatase

252

(9)

12.2.1 Designing and Synthesizing Dual-site Inhibitors

252

(1)

12.2.1.1 The Target

252

(1)

12.2.1.2 Initial Leads

252

(1)

12.2.1.3 Extension of the Initial Fragment

254

(1)

12.2.1.4 Discovery and Incorporation of the Second Fragment

256

(1)

12.2.1.5 The Search for Potency and Selectivity

257

(1)

12.2.2 Finding More "Drug-like" Molecules

258

(1)

12.2.2.1 Decreasing Polar Surface Area on Site 2

258

(1)

12.2.2.2 Monoacid Replacements on Site 1

258

(1)

12.2.2.3 Core Replacement

259

(2)

12.3 Case 2: MurF

261

(2)

12.3.1 Pre-filtering by Solution-phase NMR for Rapid Co-crystal Structure Determinations

261

(1)

12.3.1.1 The Target

261

(1)

12.3.1.2 Triage of Initial Leads

261

(1)

12.3.1.3 Solution-phase NMR as a Pre-filter for Co-crystallization Trials

262

(1)

12.4 Conclusion

263

(1)

Acknowledgments

264

(1)

References

264

(3)

13 Ligand SAR Using Electrospray Ionization Mass Spectrometry

267

(1)

Richard H. Griffey and Eric E. Swayze

13.1 Introduction

267

(1)

13.2 ES I-M S of Protein and RNA Targets

268

(3)

13.2.1 ESI-MS Data

268

(1)

13.2.2 Signal Abundances

268

(3)

13.3 Ligands Selected Using Affinity Chromatography

271

(4)

13.3.1 Antibiotics Binding Bacterial Cell Wall Peptides

272

(1)

13.3.2 Kinases and GPCRs

272

(1)

13.3.3 Src Homology 2 Domain Screening

273

(1)

13.3.4 Other Systems

274

(1)

13.4 Direct Observation of Ligand–Target Complexes

275

(7)

13.4.1 Observation of Enzyme–Ligand Transition State Complexes

276

(1)

13.4.2 Ligands Bound to Structured RNA

276

(1)

13.4.3 PSI-MS for Linking Low-affinity Ligands

277

(5)

13.5 Unique Features of ESI-MS Information for Designing Ligands

282

(1)

References

282

(3)

14 Tethering

285

(1)

Daniel A. Erlanson, Marcus D. Ballinger, and James A. Wells

14.1 Introduction

285

(1)

14.2 Energetics of Fragment Selection in Tethering

286

(3)

14.3 Practical Considerations

289

(1)

14.4 Finding Fragments

289

(4)

14.4.1 Thymidylate Synthase : Proof of Principle

289

(3)

14.4.2 Protein Tyrosine Phosphatase 1B: Finding Fragments in a Fragile, Narrow Site

292

(1)

14.5 Linking Fragments

293

(7)

14.5.1 Interleukin-2: Use of Tethering to Discover Small Molecules that Bind to a Protein–Protein Interface

293

(3)

14.5.2 Caspase-3: Finding and Combining Fragments in One Step

296

(3)

14.5.3 Caspase-1

299

(1)

14.6 Beyond Traditional Fragment Discovery

300

(6)

14.6.1 Caspase-3: Use of Tethering to Identify and Probe an Allosteric Site

300

(3)

14.6.2 GPCRs: Use of Tethering to Localize Hits and Confirm Proposed Binding Models

303

(3)

14.7 Related Approaches

306

(2)

14.7.1 Disulfide Formation

306

(1)

14.7.2 Imine Formation

307

(1)

14.7.3 Metal-mediated

307

(1)

14.8 Conclusions

308

(1)

Acknowledgments

308

(1)

References

308

(5)

Part 4: Emerging Technologies in Chemistry

15 Click Chemistry for Drug Discovery

313

(52)

Stefanie Röper and Hartmuth C. Kolb

15.1 Introduction

313

(1)

15.2 Click Chemistry Reactions

314

(2)

15.3 Click Chemistry in Drug Discovery

316

(9)

15.3.1 Lead Discovery Libraries

316

(1)

15.3.2 Natural Products Derivatives and the Search for New Antibiotics

317

(3)

15.3.3 Synthesis of Neoglycoconjugates

320

(1)

15.3.4 HIV Protease Inhibitors

321

(2)

15.3.5 Synthesis of Fucosyltranferase Inhibitor

323

(1)

15.3.6 Glycoarrays

324

(1)

15.4 In Situ Click Chemistry

325

(3)

15.4.1 Discovery of Highly Potent AChE by In Situ Click Chemistry

325

(3)

15.5 Bioconjugation Through Click Chemistry

328

(6)

15.5.1 Tagging of Live Organisms and Proteins

328

(2)

15.5.2 Activity-based Protein Profiling

330

(2)

15.5.3 Labeling of DNA

332

(1)

15.5.4 Artificial Receptors

333

(1)

15.6 Conclusion

334

(1)

References

335

(6)

16 Dynamic Combinatorial Diversity in Drug Discovery

341

(1)

Matthias Hochgürtel and Jean-Marie Lehn

16.1 Introduction

341

(1)

16.2 Dynamic Combinatorial Chemistry –The Principle

342

(1)

16.3 Generation of Diversity: DCC Reactions and Building Blocks

343

(3)

16.4 DCC Methodologies

346

(1)

16.5 Application of DCC to Biological Systems

347

(12)

16.5.1 Enzymes as Targets

349

(6)

16.5.2 Receptor Proteins as Targets

355

(2)

16.5.3 Nucleotides as Targets

357

(2)

16.6 Summary and Outlook

359

(2)

References

361

(4)

Index

365

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Fragment-based Approaches in Drug Discovery

Summary

Author Biography

Table of Contents

Supplemental Materials