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Fragment-based Approaches in Drug Discovery. Edition No. 1. Methods & Principles in Medicinal Chemistry

  • ID: 2183687
  • Book
  • August 2006
  • 391 Pages
  • John Wiley and Sons Ltd
This first systematic summary of the impact of fragment-based approaches on the drug development process provides essential information that was previously unavailable. Adopting a practice-oriented approach, this represents a book by professionals for professionals, tailor-made for drug developers in the pharma and biotech sector who need to keep up-to-date on the latest technologies and strategies in pharmaceutical ligand design. The book is clearly divided into three sections on ligand design, spectroscopic techniques, and screening and drug discovery, backed by numerous case studies.
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Preface xv

A Personal Foreword xvii

List of Contributors xix

Part I: Concept and Theory

1 The Concept of Fragment-based Drug Discovery 3
Daniel A. Erlanson and Wolfgang Jahnke

1.1 Introduction 3

1.2 Starting Small: Key Features of Fragment-based Ligand Design 4

1.2.1 FBS Samples Higher Chemical Diversity 4

1.2.2 FBS Leads to Higher Hit Rates 5

1.2.3 FBS Leads to Higher Ligand Efficiency 6

1.3 Historical Development 6

1.4 Scope and Overview of this Book 7

References 9

2 Multivalency in Ligand Design 11
Vijay M. Krishnamurthy, Lara A. Estroff, and George M. Whitesides

2.1 Introduction and Overview 11

2.2 Definitions of Terms 12

2.3 Selection of Key Experimental Studies 16

2.3.1 Trivalency in a Structurally Simple System 17

2.3.2 Cooperativity (and the Role of Enthalpy) in the “Chelate Effect“ 18

2.3.3 Oligovalency in the Design of Inhibitors to Toxins 18

2.3.4 Bivalency at Well Defined Surfaces (Self-assembled Monolayers, SAMs) 18

2.3.5 Polyvalency at Surfaces of Viruses, Bacteria, and SAMs 18

2.4 Theoretical Considerations in Multivalency 19

2.4.1 Survey of Thermodynamics 19

2.4.2 Additivity and Multivalency 19

2.4.3 Avidity and Effective Concentration (Ceff) 22

2.4.4 Cooperativity is Distinct from Multivalency 24

2.4.5 Conformational Entropy of the Linker between Ligands 25

2.4.6 Enthalpy/Entropy Compensation Reduces the Benefit of Multivalency 26

2.5 Representative Experimental Studies 26

2.5.1 Experimental Techniques Used to Examine Multivalent Systems 26

2.5.1.1 Isothermal Titration Calorimetry 26

2.5.1.2 Surface Plasmon Resonance Spectroscopy 27

2.5.1.3 Surface Assays Using Purified Components (Cell-free Assays) 27

2.5.1.4 Cell-based Surface Assays 27

2.5.2 Examination of Experimental Studies in the Context of Theory 28

2.5.2.1 Trivalency in Structurally Simple Systems 28

2.5.2.2 Cooperativity (and the Role of Enthalpy) in the “Chelate Effect“ 29

2.5.2.3 Oligovalency in the Design of Inhibitors of Toxins 29

2.5.2.4 Bivalency in Solution and at Well Defined Surfaces (SAMs) 30

2.5.2.5 Polyvalency at Surfaces (Viruses, Bacteria, and SAMs) 31

2.6 Design Rules for Multivalent Ligands 32

2.6.1 When Will Multivalency Be a Successful Strategy to Design Tight-binding Ligands? 32

2.6.2 Choice of Scaffold for Multivalent Ligands 33

2.6.2.1 Scaffolds for Oligovalent Ligands 33

2.6.2.2 Scaffolds for Polyvalent Ligands 35

2.6.3 Choice of Linker for Multivalent Ligands 36

2.6.3.1 Rigid Linkers Represent a Simple Approach to Optimize Affinity 36

2.6.3.2 Flexible Linkers Represent an Alternative Approach to Rigid Linkers to Optimize Affinity 37

2.6.4 Strategy for the Synthesis of Multivalent Ligands 37

2.6.4.1 Polyvalent Ligands: Polymerization of Ligand Monomers 38

2.6.4.2 Polyvalent Ligands: Functionalization with Ligands after Polymerization 38

2.7 Extensions of Multivalency to Lead Discovery 39

2.7.1 Hetero-oligovalency is a Broadly Applicable Concept in Ligand Design 39

2.7.2 Dendrimers Present Opportunities for Multivalent Presentation of Ligands 40

2.7.3 Bivalency in the Immune System 40

2.7.4 Polymers Could Be the Most Broadly Applicable Multivalent Ligands 42

2.8 Challenges and Unsolved Problems in Multivalency 44

2.9 Conclusions 44

Acknowledgments 45

References 45

3 Entropic Consequences of Linking Ligands 55
Christopher W. Murray and Marcel L. Verdonk

3.1 Introduction 55

3.2 Rigid Body Barrier to Binding 55

3.2.1 Decomposition of Free Energy of Binding 55

3.2.2 Theoretical Treatment of the Rigid Body Barrier to Binding 56

3.3 Theoretical Treatment of Fragment Linking 57

3.4 Experimental Examples of Fragment Linking Suitable for Analysis 59

3.5 Estimate of Rigid Body Barrier to Binding 61

3.6 Discussion 62

3.7 Conclusions 64

References 65

4 Location of Binding Sites on Proteins by the Multiple Solvent Crystal Structure Method 67
Dagmar Ringe and Carla Mattos

4.1 Introduction 67

4.2 Solvent Mapping 68

4.3 Characterization of Protein–Ligand Binding Sites 69

4.4 Functional Characterization of Proteins 71

4.5 Experimental Methods for Locating the Binding Sites of Organic Probe Molecules 71

4.6 Structures of Elastase in Nonaqueous Solvents 72

4.7 Organic Solvent Binding Sites 73

4.8 Other Solvent Mapping Experiments 75

4.9 Binding of Water Molecules to the Surface of a Protein 78

4.10 Internal Waters 79

4.11 Surface Waters 80

4.12 Conservation of Water Binding Sites 81

4.13 General Properties of Solvent and Water Molecules on the Protein 82

4.14 Computational Methods 83

4.15 Conclusion 85

Acknowledgments 85

References 85

Part 2: Fragment Library Design and Computional Approaches

5 Cheminformatics Approaches to Fragment-based Lead Discovery 91
Tudor I. Oprea and Jeffrey M. Blaney

5.1 Introduction 91

5.2 The Chemical Space of Small Molecules (Under 300 a.m.u.) 92

5.3 The Concept of Lead-likeness 94

5.4 The Fragment-based Approach in Lead Discovery 96

5.5 Literature-based Identification of Fragments: A Practical Example 99

5.6 Conclusions 107

Acknowledgments 109

References 109

6 Structural Fragments in Marketed Oral Drugs 113

Michal Vieth and Miles Siegel

6.1 Introduction 113

6.2 Historical Look at the Analysis of Structural Fragments of Drugs 113

6.3 Methodology Used in this Analysis 115

6.4 Analysis of Similarities of Different Drug Data Sets Based on the Fragment Frequencies 118

6.5 Conclusions 123

Acknowledgments 124

References 124

7 Fragment Docking to Proteins with the Multi-copy Simultaneous Search Methodology 125
Collin M. Stultz and Martin Karplus

7.1 Introduction 125

7.2 The MCSS Method 125

7.2.1 MCSS Minimizations 126

7.2.2 Choice of Functional Groups 126

7.2.3 Evaluating MCSS Minima 127

7.3 MCSS in Practice: Functionality Maps of Endothiapepsin 132

7.4 Comparison with GRID 135

7.5 Comparison with Experiment 137

7.6 Ligand Design with MCSS 138

7.6.1 Designing Peptide-based Ligands to Ras 138

7.6.2 Designing Non-peptide Based Ligands to Cytochrome P450 140

7.6.3 Designing Targeted Libraries with MCSS 140

7.7 Protein Flexibility and MCSS 141

7.8 Conclusion 143

Acknowledgments 144

References 144

Part 3: Experimental Techniques and Applications

8 NMR-guided Fragment Assembly 149
Daniel S. Sem

8.1 Historical Developments Leading to NMR-based Fragment Assembly 149

8.2 Theoretical Foundation for the Linking Effect 150

8.3 NMR-based Identification of Fragments that Bind Proteins 152

8.3.1 Fragment Library Design Considerations 152

8.3.2 The “SHAPES” NMR Fragment Library 154

8.3.3 The “SAR by NMR“ Fragment Library 156

8.3.4 Fragment-based Classification of protein Targets 160

8.4 NMR-based Screening for Fragment Binding 163

8.4.1 Ligand-based Methods 163

8.4.2 Protein-based Methods 165

8.4.3 High-throughput Screening: Traditional and TINS 167

8.5 NMR-guided Fragment Assembly 167

8.5.1 SAR by NMR 167

8.5.2 SHAPES 169

8.5.3 Second-site Binding Using Paramagnetic Probes 169

8.5.4 NMR-based Docking 170

8.6 Combinatorial NMR-based Fragment Assembly 171

8.6.1 NMR SOLVE 171

8.6.2 NMR ACE 173

8.7 Summary and Future Prospects 176

References 177

9 SAR by NMR: An Analysis of Potency Gains Realized Through Fragmentlinking and Fragment-elaboration Strategies for Lead Generation 181
Philip J. Hajduk, Jeffrey R. Huth, and Chaohong Sun

9.1 Introduction 181

9.2 SAR by NMR 182

9.3 Energetic Analysis of Fragment Linking Strategies 183

9.4 Fragment Elaboration 187

9.5 Energetic Analysis of Fragment Elaboration Strategies 188

9.6 Summary 190

References 191

10 Pyramid: An Integrated Platform for Fragment-based Drug Discovery 193
Thomas G. Davies, Rob L. M. van Montfort, Glyn Williams, and Harren Jhoti

10.1 Introduction 193

10.2 The Pyramid Process 194

10.2.1 Introduction 194

10.2.2 Fragment Libraries 195

10.2.2.1 Overview 195

10.2.2.2 Physico-chemical Properties of Library Members 196

10.2.2.3 Drug Fragment Library 197

10.2.2.4 Privileged Fragment Library 197

10.2.2.5 Targeted Libraries and Virtual Screening 197

10.2.2.6 Quality Control of Libraries 201

10.2.3 Fragment Screening 201

10.2.4 X-ray Data Collection 202

10.2.5 Automation of Data Processing 203

10.2.6 Hits and Diversity of Interactions 205

10.2.6.1 Example 1: Compound 1 Binding to CDK2 205

10.2.6.2 Example 2: Compound 2 Binding to p38_ 207

10.2.6.3 Example 3: Compound 3 Binding to Thrombin 207

10.3 Pyramid Evolution – Integration of Crystallography and NMR 207

10.3.1 NMR Screening Using Water-LOGSY 208

10.3.2 Complementarity of X-ray and NMR Screening 210

10.4 Conclusions 211

Acknowledgments 211

References 212

11 Fragment-based Lead Discovery and Optimization Using X-Ray Crystallography, Computational Chemistry, and High-throughput Organic Synthesis 215
Jeff Blaney,Vicki Nienaber, and Stephen K. Burley

11.1 Introduction 215

11.2 Overview of the SGX Structure-driven Fragment-based Lead Discovery Process 217

11.3 Fragment Library Design for Crystallographic Screening 218

11.3.1 Considerations for Selecting Fragments 218

11.3.2 SGX Fragment Screening Library Selection Criteria 219

11.3.3 SGX Fragment Screening Library Properties 220

11.3.4 SGX Fragment Screening Library Diversity: Theoretical and Experimental Analyses 220

11.4 Crystallographic Screening of the SGX Fragment Library 221

11.4.1 Overview of Crystallographic Screening 222

11.4.2 Obtaining the Initial Target Protein Structure 224

11.4.3 Enabling Targets for Crystallographic Screening 225

11.4.4 Fragment Library Screening at SGX-CAT 225

11.4.5 Analysis of Fragment Screening Results 226

11.4.6 Factor VIIa Case Study of SGX Fragment Library Screening 228

11.5 Complementary Biochemical Screening of the SGX Fragment Library 230

11.6 Importance of Combining Crystallographic and Biochemical Fragment Screening 232

11.7 Selecting Fragments Hits for Chemical Elaboration 233

11.8 Fragment Optimization 234

11.8.1 Spleen Tyrosine Kinase Case Study 234

11.8.2 Fragment Optimization Overview 240

11.8.3 Linear Library Optimization 241

11.8.4 Combinatorial Library Optimization 242

11.9 Discussion and Conclusions 243

11.10 Postscript: SGX Oncology Lead Generation Program 245

References 245

12 Synergistic Use of Protein Crystallography and Solution-phase NMR Spectroscopy in Structure-based Drug Design: Strategies and Tactics 249
Cele Abad-Zapatero, Geoffrey F. Stamper, and Vincent S. Stoll

12.1 Introduction 249

12.2 Case 1: Human Protein Tyrosine Phosphatase 252

12.2.1 Designing and Synthesizing Dual-site Inhibitors 252

12.2.1.1 The Target 252

12.2.1.2 Initial Leads 252

12.2.1.3 Extension of the Initial Fragment 254

12.2.1.4 Discovery and Incorporation of the Second Fragment 256

12.2.1.5 The Search for Potency and Selectivity 257

12.2.2 Finding More “Drug-like” Molecules 258

12.2.2.1 Decreasing Polar Surface Area on Site 2 258

12.2.2.2 Monoacid Replacements on Site 1 258

12.2.2.3 Core Replacement 259

12.3 Case 2: MurF 261

12.3.1 Pre-filtering by Solution-phase NMR for Rapid Co-crystal Structure Determinations 261

12.3.1.1 The Target 261

12.3.1.2 Triage of Initial Leads 261

12.3.1.3 Solution-phase NMR as a Pre-filter for Co-crystallization Trials 262

12.4 Conclusion 263

Acknowledgments 264

References 264

13 Ligand SAR Using Electrospray Ionization Mass Spectrometry 267
Richard H. Griffey and Eric E. Swayze

13.1 Introduction 267

13.2 ESI-MS of Protein and RNA Targets 268

13.2.1 ESI-MS Data 268

13.2.2 Signal Abundances 268

13.3 Ligands Selected Using Affinity Chromatography 271

13.3.1 Antibiotics Binding Bacterial Cell Wall Peptides 272

13.3.2 Kinases and GPCRs 272

13.3.3 Src Homology 2 Domain Screening 273

13.3.4 Other Systems 274

13.4 Direct Observation of Ligand–Target Complexes 275

13.4.1 Observation of Enzyme–Ligand Transition State Complexes 276

13.4.2 Ligands Bound to Structured RNA 276

13.4.3 ESI-MS for Linking Low-affinity Ligands 277

13.5 Unique Features of ESI-MS Information for Designing Ligands 282

References 282

14 Tethering 285
Daniel A. Erlanson, Marcus D. Ballinger, and James A. Wells

14.1 Introduction 285

14.2 Energetics of Fragment Selection in Tethering 286

14.3 Practical Considerations 289

14.4 Finding Fragments 289

14.4.1 Thymidylate Synthase: Proof of Principle 289

14.4.2 Protein Tyrosine Phosphatase 1B: Finding Fragments in a Fragile, Narrow Site 292

14.5 Linking Fragments 293

14.5.1 Interleukin-2: Use of Tethering to Discover Small Molecules that Bind to a Protein–Protein Interface 293

14.5.2 Caspase-3: Finding and Combining Fragments in One Step 296

14.5.3 Caspase-1 299

14.6 Beyond Traditional Fragment Discovery 300

14.6.1 Caspase-3: Use of Tethering to Identify and Probe an Allosteric Site 300

14.6.2 GPCRs: Use of Tethering to Localize Hits and Confirm Proposed Binding Models 303

14.7 Related Approaches 306

14.7.1 Disulfide Formation 306

14.7.2 Imine Formation 307

14.7.3 Metal-mediated 307

14.8 Conclusions 308

Acknowledgments 308

References 308

Part 4: Emerging Technologies in Chemistry

15 Click Chemistry for Drug Discovery 313
Stefanie Röper and Hartmuth C. Kolb

15.1 Introduction 313

15.2 Click Chemistry Reactions 314

15.3 Click Chemistry in Drug Discovery 316

15.3.1 Lead Discovery Libraries 316

15.3.2 Natural Products Derivatives and the Search for New Antibiotics 317

15.3.3 Synthesis of Neoglycoconjugates 320

15.3.4 HIV Protease Inhibitors 321

15.3.5 Synthesis of Fucosyltranferase Inhibitor 323

15.3.6 Glycoarrays 324

15.4 In Situ Click Chemistry 325

15.4.1 Discovery of Highly Potent AChE by In Situ Click Chemistry 325

15.5 Bioconjugation Through Click Chemistry 328

15.5.1 Tagging of Live Organisms and Proteins 328

15.5.2 Activity-based Protein Profiling 330

15.5.3 Labeling of DNA 332

15.5.4 Artificial Receptors 333

15.6 Conclusion 334

References 335

16 Dynamic Combinatorial Diversity in Drug Discovery 341
Matthias Hochgürtel and Jean-Marie Lehn

16.1 Introduction 341

16.2 Dynamic Combinatorial Chemistry –The Principle 342

16.3 Generation of Diversity: DCC Reactions and Building Blocks 343

16.4 DCC Methodologies 346

16.5 Application of DCC to Biological Systems 347

16.5.1 Enzymes as Targets 349

16.5.2 Receptor Proteins as Targets 355

16.5.3 Nucleotides as Targets 357

16.6 Summary and Outlook 359

References 361

Index 365

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Wolfgang Jahnke Novartis Pharma, Basel, Switzerland.

Daniel A. Erlanson Sunesis Pharmaceuticals, Inc., San Francisco, USA.
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