Fragment-based Drug Discovery

From its origins as a niche technique more than 15 years ago, fragment-based approaches have become a major tool for drug and ligand discovery, often yielding results where other methods have failed. Written by the pioneers in the field, this book provides a comprehensive overview of current methods and applications of fragment-based discovery, as well as an outlook on where the field is headed. The first part discusses basic considerations of when to use fragment-based methods, how to select targets, and how to build libraries in the chemical fragment space. The second part describes established, novel and emerging methods for fragment screening, including empirical as well as computational approaches. Special cases of fragment-based screening, e. g. for complex target systems and for covalent inhibitors are also discussed. The third part presents several case studies from recent and on-going drug discovery projects for a variety of target classes, from kinases and phosphatases to targeting protein-protein interaction and epigenetic targets.

Auteur
Daniel A. Erlanson is the co-founder and President of Carmot Therapeutics, Inc., which is developing fragment-based approaches to address unmet needs in drug discovery. Prior to Carmot, Dr. Erlanson worked in medicinal chemistry and technology development at Sunesis Pharmaceuticals, which he joined at the company's inception. Before Sunesis, he was an NIH postdoctoral fellow with Dr. James A. Wells at Genentech. Dr. Erlanson earned his Ph.D. in chemistry from Harvard University in the laboratory of Gregory L. Verdine and his BA in chemistry from Carleton College. He edits a blog devoted to fragment-based drug discovery, Practical Fragments.

Wolfgang Jahnke is a Director and Leading Scientist at the Novartis Institutes for Biomedical Research in Basel, Switzerland. His major interests are Structural Biophysics and Fragment-based Drug Discovery. He has received several honors, among them the Industrial Investigator Award from the Swiss Chemical Society, and several Novartis-internal Awards. Dr. Jahnke received his PhD from the TU Munchen, working with Horst Kessler on the development and application of novel NMR methods. Prior to joining Novartis, he worked with Peter Wright at the Scripps Research Institute in La Jolla.

Contenu

Contributors XV

Preface XXI

A Personal Foreword XXIII

Part I The Concept of Fragment-based Drug Discovery 1

1 The Role of Fragment-based Discovery in Lead Finding 3
Roderick E. Hubbard

1.1 Introduction 3

1.2 What is FBLD? 4

1.3 FBLD: Current Practice 5

1.3.1 Using Fragments: Conventional Targets 5

1.3.2 Using Fragments: Unconventional Targets 13

1.4 What do Fragments Bring to Lead Discovery? 14

1.5 How did We Get Here? 16

1.5.1 Evolution of the Early Ideas and History 16

1.5.2 What has Changed Since the First Book was Published in 2006? 16

1.6 Evolution of the Methods and Their Application Since 2005 19

1.6.1 Developments in Fragment Libraries 21

1.6.2 Fragment Hit Rate and Druggability 22

1.6.3 Developments in Fragment Screening 23

1.6.4 Ways of Evolving Fragments 23

1.6.5 Integrating Fragments Alongside Other Lead-Finding Strategies 23

1.6.6 Fragments Can be Selective 24

1.6.7 Fragment Binding Modes 25

1.6.8 Fragments, Chemical Space, and Novelty 27

1.7 Current Application and Impact 27

1.8 Future Opportunities 28

References 29

2 Selecting the Right Targets for Fragment-Based Drug Discovery 37
Thomas G. Davies, Harren Jhoti, Puja Pathuri, and Glyn Williams

2.1 Introduction 37

2.2 Properties of Targets and Binding Sites 39

2.3 Assessing Druggability 41

2.4 Properties of Ligands and Drugs 42

2.5 Case Studies 43

2.5.1 Case Study 1: Inhibitors of Apoptosis Proteins (IAPs) 44

2.5.2 Case Study 2: HCV-NS3 46

2.5.3 Case Study 3: PKM2 47

2.5.4 Case Study 4: Soluble Adenylate Cyclase 49

2.6 Conclusions 50

References 51

3 Enumeration of Chemical Fragment Space 57
Jean-Louis Reymond, Ricardo Visini, and Mahendra Awale

3.1 Introduction 57

3.2 The Enumeration of Chemical Space 58

3.2.1 Counting and Sampling Approaches 58

3.2.2 Enumeration of the Chemical Universe Database GDB 58

3.2.3 GDB Contents 59

3.3 Using and Understanding GDB 61

3.3.1 Drug Discovery 61

3.3.2 The MQN System 62

3.3.3 Other Fingerprints 63

3.4 Fragments from GDB 65

3.4.1 Fragment Replacement 65

3.4.2 Shape Diversity of GDB Fragments 66

3.4.3 Aromatic Fragments from GDB 68

3.5 Conclusions and Outlook 68

Acknowledgment 69

References 69

4 Ligand Efficiency Metrics and their Use in Fragment Optimizations 75
György G. Ferenczy and György M. Keseru

4.1 Introduction 75

4.2 Ligand Efficiency 75

4.3 Binding Thermodynamics and Efficiency Indices 78

4.4 Enthalpic Efficiency Indices 81

4.5 Lipophilic Efficiency Indices 83

4.6 Application of Efficiency Indices in Fragment-Based Drug Discovery Programs 88

4.7 Conclusions 94

References 95

Part II Methods and Approaches for Fragment-based Drug Discovery 99

5 Strategies for Fragment Library Design 101
Justin Bower, Angelo Pugliese, and Martin Drysdale

5.1 Introduction 101

5.2 Aims 102

5.3 Progress 102

5.3.1 BDDP Fragment Library Design: Maximizing Diversity 103

5.3.2 Assessing Three-Dimensionality 103

5.3.3 3DFrag Consortium 104

5.3.4 Commercial Fragment Space Analysis 105

5.3.5 BDDP Fragment Library Design 108

5.3.6 Fragment Complexity 111

5.3.6.1 Diversity-Oriented Synthesis-Derived Fragment-Like Molecules 113

5.4 Future Plans 114

5.5 Summary 116

5.6 Key Achievements 116

References 116 **6 The Synthesis of Biophysical Methods I...