Structure-based drug discovery : an overview

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Publication Information:

Cambridge, UK : The Royal Society of Chemistry, 2006

ISBN:

9780854043514

Subject Term:

Drugs -- Design

Drugs -- Structure-activity relationships

Added Author:

Hubbard, Roderick E.

Added Corporate Author:

Royal Society of Chemistry (Great Britain)

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Library	Item Barcode	Call Number	Material Type	Item Category 1	Status
Searching... PSZ JB	30000010119416	RS420 S77 2006	Open Access Book	Book	Searching... Unknown

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. After an introductory overview of the principles and application of structure-based methods in drug discovery, this book then describes the essential features of the various methods. Chapters on X-ray crystallography, NMR spectroscopy, and computational chemistry and molecular modelling describe how these particular techniques have been enhanced to support rational drug discovery, with discussions on developments such as high throughput structure determination, probing protein-ligand interactions by NMR spectroscopy, virtual screening and fragment-based drug discovery. The concluding chapters complement the overview of methods by presenting case histories to demonstrate the major impact that structure-based methods have had on discovering drug molecules. Written by international experts from industry and academia, this comprehensive introduction to the methods and practice of structure-based drug discovery not only illustrates leading-edge science but also provides the scientific background for the non-expert reader. The book provides a balanced appraisal of what structure-based methods can and cannot contribute to drug discovery. It will appeal to industrial and academic researchers in pharmaceutical sciences, medicinal chemistry and chemical biology, as well as providing an insight into the field for recent graduates in the biomolecular sciences.

Roderick E. HubbardDavid G. Brown and Maria M. FloccoXavier Barril and Robert SolivaBen Davis and Julia HubbardAndrew R. Leach and Michael M. Hann and Jeremy N. Burrows and Ed GriffenJohn W. Liebeschuetz and Stuart D. Jones and Michael R. Wiley and Steven C. YoungPeter ColmanEric S. Manas and Richard E. Mewshaw and Heather A. Harris and Michael S. Malamas

Chapter 1 3D Structure and the Drug Discovery Process	p. 1
1 Introduction	p. 1
2 The Drug Discovery Process	p. 2
2.1 Establishing a Target	p. 3
2.2 Hit Identification	p. 5
2.3 Hits to Leads	p. 6
2.4 Lead Optimisation	p. 7
2.5 Pre-Clinical Trials	p. 8
2.6 Clinical Trials	p. 8
2.7 Maintaining the Pipeline	p. 9
3 What is Structure-Based Drug Discovery?	p. 9
3.1 From Hype to Application	p. 9
3.2 Structural Biology	p. 10
3.3 Structure-Based Design	p. 11
3.4 Structure-Based Discovery	p. 12
4 The Evolution of the Ideas of Structure-Based Drug Discovery	p. 13
4.1 1960s	p. 13
4.2 1970s	p. 14
4.3 1980s	p. 16
4.4 1990s	p. 17
4.5 2000s	p. 19
5 What isn't in this Book	p. 20
5.1 Drug Discovery Against GPCR Targets	p. 20
5.2 Protein-Protein Interactions	p. 21
5.3 Using Structural Models of ADMET Mechanisms	p. 21
5.4 Protein Therapeutics	p. 22
5.5 Other Targets for Structure-Based Drug Discovery	p. 22
6 Concluding Remarks	p. 23
References	p. 24
Chapter 2 Structure Determination - Crystallography for Structure-Based Drug Discovery	p. 32
1 What is X-ray Crystallography?	p. 32
2 What is Required to Produce a Crystal Structure?	p. 35
3 Crystallisability of Proteins	p. 36
4 How does the X-ray Data Relate to the Electron Density? - The Phase Problem	p. 36
5 Electron Density Map Interpretation and Atomic Model of the Protein	p. 37
6 Useful Crystallographic Terminology when Utilising Crystal Structures	p. 38
7 The Clone-to-Structure Process and SBDD	p. 39
8 Recent Technological Advances	p. 39
9 The Role of Crystal Structures in the Discovery Process	p. 42
10 The Optimal SBDD System	p. 43
11 Producing a Biologically Relevant Structure	p. 44
12 Phosphorylation	p. 44
13 Glycosylation - Balancing Solubility with Crystallisability	p. 45
14 Engineering Solubility	p. 46
15 Specific Crystal Packing Engineering	p. 46
16 Engineering Stability	p. 47
17 Use of Surrogate Proteins	p. 47
18 The Impact of Structural Genomics	p. 48
References	p. 49
Chapter 3 Molecular Modelling	p. 54
1 Introduction	p. 54
2 Methods	p. 55
2.1 Quantum Chemistry Methods	p. 55
2.1.1 Ligand Internal Energy	p. 56
2.1.2 Study of Reactivity	p. 57
2.1.3 Ligand-Receptor Interaction Energy	p. 57
2.2 Parametric Methods	p. 58
2.2.1 Force-Fields	p. 58
2.2.2 Empirical Scoring Functions	p. 59
2.2.3 Statistical Potentials	p. 60
2.3 Solvation	p. 60
2.4 Sampling Algorithms	p. 61
3 Applications	p. 63
3.1 Target Evaluation	p. 63
3.1.1 Target Druggability	p. 54
3.1.2 Structure Availability and Critical Assessment	p. 67
3.2 Hit Finding	p. 69
3.2.1 Docking	p. 69
3.2.2 De novo Design	p. 72
3.2.3 The Role of Chemoinformatics	p. 73
3.2.4 Integrative VS	p. 73
3.2.5 Template or Scaffold Hopping	p. 75
3.2.6 Target Hopping	p. 76
3.3 Hit to Lead	p. 77
3.3.1 Binding Mode Determination	p. 77
3.3.2 Improving the Potency of the Hit	p. 78
3.3.3 Modulation of ADMET properties	p. 83
4 Conclusion	p. 84
References	p. 85
Chapter 4 Applications of NMR in Structure-Based Drug Discovery	p. 97
1 Introduction	p. 97
1.1 The Role of NMR in SBDD	p. 98
2 Studying Ligand-Receptor Interactions by NMR	p. 98
2.1 Detecting Ligand Binding	p. 98
2.2 Ligand-Based and Receptor-Based Screening	p. 100
2.3 Ligand-Based Approaches	p. 101
2.3.1 Filtered Experiments	p. 101
2.3.2 Magnetization Transfer Experiments	p. 105
2.3.3 Fluorine-Detected Experiments	p. 112
2.3.4 Ligand Displacement by a Known Competitor	p. 113
2.4 Receptor-Based Approaches	p. 114
2.4.1 Selective Labeling Strategies	p. 115
2.4.2 Larger Proteins	p. 116
2.4.3 [superscript 13]C labeling	p. 117
2.5 Examples of NMR-Screening Approaches	p. 117
2.5.1 Stromelysin	p. 118
2.5.2 Jnk3	p. 119
2.5.3 DNA Gyrase	p. 119
3 NMR in Structure-Based Lead Optimization	p. 120
3.1 Practical Aspects of Ligand-Receptor Complexes	p. 121
3.1.1 Determining Which NMR Approach to Use	p. 121
3.1.2 Methods for Preparation of the Complex	p. 121
3.2 NMR Methods for Characterizing Bound Ligands	p. 122
3.2.1 NMR Approaches for Ligand-Receptor Complexes in Fast Exchange	p. 122
3.2.2 NMR Approaches for Ligand/Receptor Complexes in Slow Exchange	p. 127
3.3 Chemical-Shift-Based Approaches Combined with Docking	p. 129
4 Other Applications of NMR in SBDD	p. 131
4.1 NMR in Protein Production	p. 131
4.2 Protein Structure Determination by NMR	p. 132
5 Conclusion and Outlook	p. 132
References	p. 134
Chapter 5 Fragment Screening: An Introduction	p. 142
1 Introduction	p. 142
2 The Concept of Drug-Likeness	p. 142
3 The Evolution of Lead-Likeness and Fragment Screening	p. 144
4 Finding Fragments by Screening	p. 154
4.1 High Concentration Screening using a Biochemical Assay	p. 155
4.2 Biophysical and Direct Structure Determination Screening	p. 155
4.2.1 Screening by Crystallography	p. 155
4.2.2 Screening by Other Biophysical Methods	p. 156
5 The Design of Fragment Screening Sets	p. 156
6 Turning Fragment Hits into Leads	p. 161
6.1 Fragment Evolution	p. 162
6.2 Fragment Linking	p. 163
6.3 Fragment Self-Assembly	p. 165
6.4 Fragment Optimisation	p. 166
7 Summary	p. 167
References	p. 169
Chapter 6 Iterative Structure-Based Screening of Virtual Chemical Libraries and Factor Xa: Finding the Orally Available Antithrombotic Candidate LY517717	p. 173
1 Introduction	p. 173
2 Morphology of the Factor Xa Active Site	p. 175
3 Structure-Based Library Design	p. 176
4 Design Strategy for Factor Xa	p. 178
5 Introducing Oral Availability	p. 182
6 Non-Basic S1 Series	p. 187
7 Oral Antithrombotic Activity	p. 188
8 Conclusion	p. 190
Acknowledgements	p. 191
References	p. 191
Chapter 7 Anti-Influenza Drugs from Neuraminidase Inhibitors	p. 193
1 Introduction	p. 193
2 Influenza Viruses	p. 193
3 Early Attempts to Discover Neuraminidase Inhibitors	p. 196
4 Neuraminidase Structure	p. 196
5 Structure-Based Discovery of Inhibitors	p. 199
5.1 Zanamivir	p. 199
5.2 Analogues of Zanamivir	p. 200
5.3 Oseltamivir	p. 203
5.4 BCX1812 (RWJ270201)	p. 203
5.5 A315675	p. 205
5.6 Benzoic Acid Frameworks	p. 206
6 Retrospective Analyses of Inhibitor-Binding	p. 206
7 Laboratory Studies of Inhibitor Resistant Variants	p. 207
8 Clinical Studies of Drug Resistance	p. 208
9 Drug Profiles	p. 209
9.1 Pharmacology	p. 209
9.2 Efficacy in Therapy	p. 210
9.3 Efficacy in Prophylaxis	p. 210
9.4 Safety	p. 211
9.5 Current Approval Status	p. 211
10 Conclusions	p. 211
References	p. 212
Chapter 8 Isoform Specificity: The Design of Estrogen Receptor-[beta] Selective Compounds	p. 219
1 Introduction	p. 219
2 Structure-Based Design Methodology	p. 222
2.1 Initial Considerations	p. 222
2.2 Docking Calculations	p. 224
2.3 Quantum Chemical Calculations	p. 225
2.4 Interpretation of Structural Information	p. 227
3 The Design of Aryl Diphenolic Azoles As ER[beta] Selective Agonists	p. 229
3.1 Phenyl and Naphthyl Isoxazoles	p. 229
3.2 Phenyl and Naphthyl Benzoxazoles	p. 232
4 Learning From and Moving Beyond the Genistein Scaffold	p. 236
4.1 Biphenyl Scaffolds	p. 236
4.2 Phenyl Napthalenes	p. 238
4.3 Constrained Phenyl-Naphthalene Analogs: Dibenzochromenes	p. 244
5 Evaluation of ER[beta] Selective Compounds in Biological Assays	p. 245
6 Conclusions	p. 249
Acknowledgments	p. 250
References	p. 250
Subject Index	p. 257

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