Structure-Based Drug Discovery An Overview Edited by Roderick E. Hubbard University of York, Heslington, York, UK and Vernalis (R&D) Ltd, Abington, Cambridge, UK RSC Publishing
Contents Chapter 1 3D Structure and the Drug Discovery Process 1 Roderick E. Hubbard 1 Introduction 1 2 The Drug Discovery Process 2 2.1 Establishing a Target 3 2.2 Hit Identification 5 2.3 Hits to Leads 6 2.4 Lead Optimisation 7 2.5 Pre-Clinical Trials 8 2.6 Clinical Trials 8 2.7 Maintaining the Pipeline 9 3 What is Structure-Based Drug Discovery? 9 3.1 From Hype to Application 9 3.2 Structural Biology 10 3.3 Structure-Based Design 11 3.4 Structure-Based Discovery 12 4 The Evolution of the Ideas of Structure-Based Drug Discovery 13 4.1 1960s 13 4.2 1970s 14 4.3 1980s 16 4.4 1990s 17 4.5 2000s 19 5 What isn't in this Book 20 5.1 Drug Discovery Against GPCR Targets 20 5.2 Protein-Protein Interactions 21 5.3 Using Structural Models of ADMET Mechanisms 21 5.4 Protein Therapeutics 22 5.5 Other Targets for Structure-Based Drug Discovery 22 6 Concluding Remarks 23 References 24
xjj Contents Chapter 2 Structure Determination - Crystallography for Structure-Based Drug Discovery 32 David G. Brown and Maria M. Flocco 1 What is X-ray Crystallography? 32 2 What is Required to Produce a Crystal Structure? 35 3 Crystallisability of Proteins 36 4 How does the X-ray Data Relate to the Electron Density? - The Phase Problem 36 5 Electron Density Map Interpretation and Atomic Model of the Protein 37 6 Useful Crystallographic Terminology when Utilising Crystal Structures 38 7 The Clone-to-Structure Process and SBDD 39 8 Recent Technological Advances 39 9 The Role of Crystal Structures in the Discovery Process 42 10 The Optimal SBDD System 43 11 Producing a Biologically Relevant Structure 44 12 Phosphorylation 44 13 Glycosylation - Balancing Solubility with Crystallisability 45 14 Engineering Solubility 46 15 Specific Crystal Packing Engineering 46 16 Engineering Stability 47 17 Use of Surrogate Proteins 47 18 The Impact of Structural Genomics 48 References 49 Chapter 3 Molecular Modelling 54 Xavier Barril and Robert Soliva 1 Introduction 54 2 Methods 55 2.1 Quantum Chemistry Methods 55 2.1.1 Ligand Internal Energy 56 2.1.2 Study of Reactivity 57 2.1.3 Ligand-Receptor Interaction Energy 57 2.2 Parametric Methods 58 2.2.1 Force-Fields 58 2.2.2 Empirical Scoring Functions 59 2.2.3 Statistical Potentials 60 2.3 Solvation 60 2.4 Sampling Algorithms 61
Contents Chapter 4 3 Applications 63 3.1 Target Evaluation 63 3.1.1 Target Druggability 64 3.1.2 Structure Availability and Critical Assessment 67 3.2 Hit Finding 69 3.2.1 Docking 69 3.2.2 De novo Design 72 3.2.3 The Role of Chemoinformatics 73 3.2.4 Integrative VS 73 3.2.5 Template or Scaffold Hopping 75 3.2.6 Target Hopping 76 3.3 Hit to Lead 77 3.3.1 Binding Mode Determination 77 3.3.2 Improving the Potency of the Hit 78 3.3.3 Modulation of ADMET properties 83 4 Conclusion 84 References 85 Applications of NMR in Structure-Based Drug Discovery 97 Ben Davis and Julia Hubbard 1 Introduction 97 1.1 The Role of NMR in SBDD 98 2 Studying Ligand-Receptor Interactions by NMR 98 2.1 Detecting Ligand Binding 98 2.2 Ligand-Based and Receptor-Based Screening 100 2.3 Ligand-Based Approaches 101 2.3.1 Filtered Experiments 101 2.3.2 Magnetization Transfer Experiments 105 2.3.3 Fluorine-Detected Experiments 112 2.3.4 Ligand Displacement by a Known Competitor 113 2.4 Receptor-Based Approaches 114 2.4.1 Selective Labeling Strategies 115 2.4.2 Larger Proteins 116 2.4.3 13 C labeling 117 2.5 Examples of NMR-Screening Approaches 117 2.5.1 Stromelysin 118 2.5.2 Jnk3 119 2.5.3 DNAGyrase 119 X]l]
xiv Contents 3 NMR in Structure-Based Lead Optimization 120 3.1 Practical Aspects of Ligand-Receptor Complexes 121 3.1.1 Determining Which NMR Approach to Use 121 3.1.2 Methods for Preparation of the Complex 121 3.2 NMR Methods for Characterizing Bound Ligands 122 3.2.1 NMR Approaches for Ligand-Receptor Complexes in Fast Exchange 122 3.2.2 NMR Approaches for Ligand/Receptor Complexes in Slow Exchange 127 3.3 Chemical-Shift-Based Approaches Combined with Docking 129 4 Other Applications of NMR in SBDD 131 4.1 NMR in Protein Production 131 4.2 Protein Structure Determination by NMR 132 5 Conclusion and Outlook 132 References 134 Chapter 5 Fragment Screening: An Introduction 142 Andrew R. Leach, Michael M. Hann, Jeremy N. Burrows and Ed Griffen 1 Introduction 142 2 The Concept of Drug-Likeness 142 3 The Evolution of Lead-Likeness and Fragment Screening 144 4 Finding Fragments by Screening 154 4.1 High Concentration Screening using a Biochemical Assay 155 4.2 Biophysical and Direct Structure Determination Screening 155 4.2.1 Screening by Crystallography 155 4.2.2 Screening by Other Biophysical Methods 156 5 The Design of Fragment Screening Sets 156 6 Turning Fragment Hits into Leads 161 6.1 Fragment Evolution 162 6.2 Fragment Linking 163 6.3 Fragment Self-Assembly 165 6.4 Fragment Optimisation 166 7 Summary 167 References 169
Contents Chapter 6 Iterative Structure-Based Screening of Virtual Chemical Libraries and Factor Xa: Finding the Orally Available Antithrombotic Candidate LY517717 173 John W. Liebeschuetz, Stuart D. Jones, Michael R. Wiley and Steven C. Young 1 Introduction 173 2 Morphology of the Factor Xa Active Site 175 3 Structure-Based Library Design 176 4 Design Strategy for Factor Xa 178 5 Introducing Oral Availability 182 6 Non-Basic SI Series 187 7 Oral Antithrombotic Activity 188 8 Conclusion 190 Acknowledgements 191 References 191 xv Chapter 7 Anti-Influenza Drugs from Neuraminidase Inhibitors 193 Peter Colman 1 Introduction 193 2 Influenza Viruses 193 3 Early Attempts to Discover Neuraminidase Inhibitors 196 4 Neuraminidase Structure 196 5 Structure-Based Discovery of Inhibitors 199 5.1 Zanamivir 199 5.2 Analogues of Zanamivir 200 5.3 Oseltamivir 203 5.4 BCX1812(RWJ270201) 203 5.5 A315675 205 5.6 Benzoic Acid Frameworks 206 6 Retrospective Analyses of Inhibitor-Binding 206 7 Laboratory Studies of Inhibitor Resistant Variants 207 8 Clinical Studies of Drug Resistance 208 9 Drug Profiles 209 9.1 Pharmacology 209 9.2 Efficacy in Therapy 210 9.3 Efficacy in Prophylaxis 210 9.4 Safety 211 9.5 Current Approval Status 211 10 Conclusions 2I1 References 21 -
Chapter 8 Contents Isoform Specificity: The Design of Estrogen Receptor-/? Selective Compounds 219 Eric S. Manas, Richard E. Mewshaw, Heather A. Harris, and Michael S. Malamas 1 Introduction 2 Structure-Based Design Methodology 2.1 Initial Considerations 2.2 Docking Calculations 2.3 Quantum Chemical Calculations 2.4 Interpretation of Structural Information 3 The Design of Aryl Diphenolic Azoles As ER/2 Selective Agonists 3.1 Phenyl and Naphthyl Isoxazoles 3.2 Phenyl and Naphthyl Benzoxazoles 4 Learning From and Moving Beyond the Genistein Scaffold 4.1 Biphenyl Scaffolds 4.2 Phenyl Napthalenes 4.3 Constrained Phenyl-Naphthalene Analogs: Dibenzochromenes 5 Evaluation of ER/3 Selective Compounds in Biological Assays 6 Conclusions Acknowledgments References 219 222 222 224 225 227 229 229 232 236 236 238 244 245 249 250 250 Subject Index 257