Structure-Based Drug Discovery An Overview

Transcription

1 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

2 Contents Chapter 1 3D Structure and the Drug Discovery Process 1 Roderick E. Hubbard 1 Introduction 1 2 The Drug Discovery Process Establishing a Target Hit Identification Hits to Leads Lead Optimisation Pre-Clinical Trials Clinical Trials Maintaining the Pipeline 9 3 What is Structure-Based Drug Discovery? From Hype to Application Structural Biology Structure-Based Design Structure-Based Discovery 12 4 The Evolution of the Ideas of Structure-Based Drug Discovery s s s s s 19 5 What isn't in this Book Drug Discovery Against GPCR Targets Protein-Protein Interactions Using Structural Models of ADMET Mechanisms Protein Therapeutics Other Targets for Structure-Based Drug Discovery 22 6 Concluding Remarks 23 References 24

3 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 The Optimal SBDD System Producing a Biologically Relevant Structure Phosphorylation Glycosylation - Balancing Solubility with Crystallisability Engineering Solubility Specific Crystal Packing Engineering Engineering Stability Use of Surrogate Proteins The Impact of Structural Genomics 48 References 49 Chapter 3 Molecular Modelling 54 Xavier Barril and Robert Soliva 1 Introduction 54 2 Methods Quantum Chemistry Methods Ligand Internal Energy Study of Reactivity Ligand-Receptor Interaction Energy Parametric Methods Force-Fields Empirical Scoring Functions Statistical Potentials Solvation Sampling Algorithms 61

4 Contents Chapter 4 3 Applications Target Evaluation Target Druggability Structure Availability and Critical Assessment Hit Finding Docking De novo Design The Role of Chemoinformatics Integrative VS Template or Scaffold Hopping Target Hopping Hit to Lead Binding Mode Determination Improving the Potency of the Hit 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 The Role of NMR in SBDD 98 2 Studying Ligand-Receptor Interactions by NMR Detecting Ligand Binding Ligand-Based and Receptor-Based Screening Ligand-Based Approaches Filtered Experiments Magnetization Transfer Experiments Fluorine-Detected Experiments Ligand Displacement by a Known Competitor Receptor-Based Approaches Selective Labeling Strategies Larger Proteins C labeling Examples of NMR-Screening Approaches Stromelysin Jnk DNAGyrase 119 X]l]

5 xiv Contents 3 NMR in Structure-Based Lead Optimization Practical Aspects of Ligand-Receptor Complexes Determining Which NMR Approach to Use Methods for Preparation of the Complex NMR Methods for Characterizing Bound Ligands NMR Approaches for Ligand-Receptor Complexes in Fast Exchange NMR Approaches for Ligand/Receptor Complexes in Slow Exchange Chemical-Shift-Based Approaches Combined with Docking Other Applications of NMR in SBDD NMR in Protein Production Protein Structure Determination by NMR 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 The Concept of Drug-Likeness The Evolution of Lead-Likeness and Fragment Screening Finding Fragments by Screening High Concentration Screening using a Biochemical Assay Biophysical and Direct Structure Determination Screening Screening by Crystallography Screening by Other Biophysical Methods The Design of Fragment Screening Sets Turning Fragment Hits into Leads Fragment Evolution Fragment Linking Fragment Self-Assembly Fragment Optimisation Summary 167 References 169

6 Contents Chapter 6 Iterative Structure-Based Screening of Virtual Chemical Libraries and Factor Xa: Finding the Orally Available Antithrombotic Candidate LY John W. Liebeschuetz, Stuart D. Jones, Michael R. Wiley and Steven C. Young 1 Introduction Morphology of the Factor Xa Active Site Structure-Based Library Design Design Strategy for Factor Xa Introducing Oral Availability Non-Basic SI Series Oral Antithrombotic Activity Conclusion 190 Acknowledgements 191 References 191 xv Chapter 7 Anti-Influenza Drugs from Neuraminidase Inhibitors 193 Peter Colman 1 Introduction Influenza Viruses Early Attempts to Discover Neuraminidase Inhibitors Neuraminidase Structure Structure-Based Discovery of Inhibitors Zanamivir Analogues of Zanamivir Oseltamivir BCX1812(RWJ270201) A Benzoic Acid Frameworks Retrospective Analyses of Inhibitor-Binding Laboratory Studies of Inhibitor Resistant Variants Clinical Studies of Drug Resistance Drug Profiles Pharmacology Efficacy in Therapy Efficacy in Prophylaxis Safety Current Approval Status Conclusions 2I1 References 21 -

7 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 Subject Index 257