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Bioisosteres in Medicinal Chemistry

Nathan Brown (Editor), Raimund Mannhold (Series Editor), Hugo Kubinyi (Series Editor), Gerd Folkers (Series Editor)
ISBN: 978-3-527-33015-7
256 pages
October 2012
Bioisosteres in Medicinal Chemistry (3527330151) cover image
Written with the practicing medicinal chemist in mind, this is the first modern handbook to systematically address the topic of bioisosterism.
As such, it provides a ready reference on the principles and methods of bioisosteric replacement as a key tool in preclinical drug development.

The first part provides an overview of bioisosterism, classical bioisosteres and typical molecular interactions that need to be considered,
while the second part describes a number of molecular databases as sources of bioisosteric identification and rationalization. The third part
covers the four key methodologies for bioisostere identification and replacement: physicochemical properties, topology, shape, and overlays of
protein-ligand crystal structures. In the final part, several real-world examples of bioisosterism in drug discovery projects are discussed.

With its detailed descriptions of databases, methods and real-life case studies, this is tailor-made for busy industrial researchers with little time for reading, while remaining easily accessible to novice drug developers due to its systematic structure and introductory section.
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List of Contributors XI

Preface XV

A Personal Foreword XVII

Part One Principles 1

1 Bioisosterism in Medicinal Chemistry 3
Nathan Brown

1.1 Introduction 3

1.2 Isosterism 3

1.3 Bioisosterism 6

1.4 Bioisosterism in Lead Optimization 9

1.5 Conclusions 13

References 14

2 Classical Bioisosteres 15
Caterina Barillari and Nathan Brown

2.1 Introduction 15

2.2 Historical Background 15

2.3 Classical Bioisosteres 17

2.4 Nonclassical Bioisosteres 20

2.5 Summary 27

References 27

3 Consequences of Bioisosteric Replacement 31
Dennis A. Smith and David S. Millan

3.1 Introduction 31

3.2 Bioisosteric Groupings to Improve Permeability 32

3.3 Bioisosteric Groupings to Lower Intrinsic Clearance 40

3.4 Bioisosteric Groupings to Improve Target Potency 43

3.5 Conclusions and Future Perspectives 47

References 49

Part Two Data 53

4 BIOSTER: A Database of Bioisosteres and Bioanalogues 55
István Ujváry and Julian Hayward

4.1 Introduction 55

4.2 Historical Overview and the Development of BIOSTER 56

4.3 Description of BIOSTER Database 59

4.4 Examples 64

4.5 Applications 69

4.6 Summary 70

4.7 Appendix 70

References 71

5 Mining the Cambridge Structural Database for Bioisosteres 75
Colin R. Groom, Tjelvar S. G. Olsson, John W. Liebeschuetz, David A. Bardwell, Ian J. Bruno, and Frank H. Allen

5.1 Introduction 75

5.2 The Cambridge Structural Database 76

5.3 The Cambridge Structural Database System 78

5.4 The Relevance of the CSD to Drug Discovery 83

5.5 Assessing Bioisosteres: Conformational Aspects 84

5.6 Assessing Bioisosteres: Nonbonded Interactions 86

5.7 Finding Bioisosteres in the CSD: Scaffold Hopping and Fragment Linking 91

5.8 A Case Study: Bioisosterism of 1H-Tetrazole and Carboxylic Acid Groups 94

5.9 Conclusions 97

References 98

6 Mining for Context-Sensitive Bioisosteric Replacements in Large Chemical Databases 103
George Papadatos, Michael J. Bodkin, Valerie J. Gillet, and Peter Willett

6.1 Introduction 103

6.2 Definitions 104

6.3 Background 105

6.4 Materials and Methods 109

6.5 Results and Discussion 113

6.6 Conclusions 124

References 125

Part Three Methods 129

7 Physicochemical Properties 131
Peter Ertl

7.1 Introduction 131

7.2 Methods to Identify Bioisosteric Analogues 132

7.3 Descriptors to Characterize Properties of Substituents and Spacers 132

7.4 Classical Methods for Navigation in the Substituent Space 135

7.5 Tools to Identify Bioisosteric Groups Based on Similarity in Their Properties 136

7.6 Conclusions 138

References 138

8 Molecular Topology 141
Nathan Brown

8.1 Introduction 141

8.2 Controlled Fuzziness 141

8.3 Graph Theory 142

8.4 Data Mining 144

8.5 Topological Pharmacophores 146

8.6 Reduced Graphs 149

8.7 Summary 151

References 152

9 Molecular Shape 155
Pedro J. Ballester and Nathan Brown

9.1 Methods 156

9.2 Applications 161

9.3 Future Prospects 164

References 165

10 Protein Structure 167
James E. J. Mills

10.1 Introduction 167

10.2 Database of Ligand–Protein Complexes 168

10.3 Generation of Ideas for Bioisosteres 173

10.4 Context-Specific Bioisostere Generation 177

10.5 Using Structure to Understand Common Bioisosteric Replacements 178

10.6 Conclusions 180

References 180

Part Four Applications 183

11 The Drug Guru Project 185
Kent D. Stewart, Jason Shanley, Karam B. Alsayyed Ahmed, and J. Phillip Bowen

11.1 Introduction 185

11.2 Implementation of Drug Guru 187

11.3 Bioisosteres 188

11.4 Application of Drug Guru 194

11.5 Quantitative Assessment of Drug Guru Transformations 195

11.6 Related Work 197

11.7 Summary: The Abbott Experience with the Drug Guru Project 197

References 198

12 Bioisosteres of an NPY-Y5 Antagonist 199
Nicholas P. Barton and Benjamin R. Bellenie

12.1 Introduction 199

12.2 Background 199

12.3 Potential Bioisostere Approaches 201

12.4 Template Molecule Preparation 204

12.5 Database Molecule Preparation 206

12.6 Alignment and Scoring 206

12.7 Results and Monomer Selection 207

12.8 Synthesis and Screening 208

12.9 Discussion 209

12.10 SAR and Developability Optimization 211

12.11 Summary and Conclusion 214

References 214

13 Perspectives from Medicinal Chemistry 217
Nicholas A. Meanwell, Marcus Gastreich, Matthias Rarey, Mike Devereux, Paul L.A. Popelier, Gisbert Schneider, and Peter Willett

13.1 Introduction 217

13.2 Pragmatic Bioisostere Replacement in Medicinal Chemistry: A Software Maker’s Viewpoint 219

13.3 The Role of Quantum Chemistry in Bioisostere Prediction 221

13.4 Learn from ‘‘Naturally Drug-Like’’ Compounds 223

13.5 Bioisosterism at the University of Sheffield 224

References 227

Index 231

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Nathan Brown is the Head of the In Silico Medicinal Chemistry group in the Cancer Therapeutics Unit at The Institute of Cancer Research in London (UK). At the ICR, Nathan and his group support our entire drug discovery portfolio together with developing new computational methodologies to enhance our drug design work.
Nathan conducted his doctoral research in Sheffield with Professor Peter Willett focusing on evolutionary algorithms and graph theory. After a two-year Marie Curie fellowship in Amsterdam in collaboration with Professor Johann Gasteiger in Erlangen, he joined the Novartis Institutes for BioMedical Research in Basel for a three-year Presidential fellowship in Basel working with Professors Peter Willett and Karl-Heinz Altmann.
Nathan?s work has led to the pioneering work on mulitobjective de novo design in addition to a variety of discoveries and method development in bioisosteric identification and replacement, scaffold hopping, molecular descriptors and statistical modelling. Nathan continues to pursue his research in all aspects of in silico medicinal chemistry.
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“In all, I believe this book is a musthave handbook on bioisosteres. It is highly valuable both as a text book for graduate students and as a book of reference for the medicinal chemist working in the industry as well as in an academic setting.”  (ChemMedChem, 1 July 2013)

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