Bioisosteres in Medicinal Chemistry by Brown, Nathan -- Read -- Imperial Library of Trantor

Index

Bioisosteres in Medicinal Chemistry

Contents List of Contributors Preface A Personal Foreword Part One: Principles

1 Bioisosterism in Medicinal Chemistry

1.1 Introduction 1.2 Isosterism 1.3 Bioisosterism 1.4 Bioisosterism in Lead Optimization

1.4.1 Common Replacements in Medicinal Chemistry 1.4.2 Structure-Based Drug Design 1.4.3 Multiobjective Optimization

1.5 Conclusions References

2 Classical Bioisosteres

2.1 Introduction 2.2 Historical Background 2.3 Classical Bioisosteres

2.3.1 Monovalent Atoms and Groups 2.3.2 Bivalent Atoms and Groups 2.3.3 Trivalent Atoms and Groups 2.3.4 Tetravalent Atoms 2.3.5 Ring Equivalents

2.4 Nonclassical Bioisosteres

2.4.1 Carbonyl Group 2.4.2 Carboxylic Acid 2.4.3 Hydroxyl Group 2.4.4 Catechol 2.4.5 Halogens 2.4.6 Amide and Esters 2.4.7 Thiourea 2.4.8 Pyridine 2.4.9 Cyclic Versus Noncyclic Systems

2.5 Summary References

3 Consequences of Bioisosteric Replacement

3.1 Introduction 3.2 Bioisosteric Groupings to Improve Permeability 3.3 Bioisosteric Groupings to Lower Intrinsic Clearance 3.4 Bioisosteric Groupings to Improve Target Potency 3.5 Conclusions and Future Perspectives References

Part Two: Data

4 BIOSTER: A Database of Bioisosteres and Bioanalogues

4.1 Introduction 4.2 Historical Overview and the Development of BIOSTER

4.2.1 Representation of Chemical Transformations for Reaction Databases 4.2.2 The Concept of ‘‘Biosteric Transformation’’ 4.2.3 Other Analogue and Bioisostere Databases

4.3 Description of BIOSTER Database

4.3.1 Coverage and Selection Criteria 4.3.2 Sources 4.3.3 Description of the Layout of Database Records

4.3.3.1 ID Code 4.3.3.2 Biosteric Transformation 4.3.3.3 Citation(s) 4.3.3.4 Activity 4.3.3.5 Fragments 4.3.3.6 Component Molecules and Fragments

4.4 Examples

4.4.1 Benzodioxole Bioisosteres 4.4.2 Phenol Bioisosteres 4.4.3 Ketoamides

4.5 Applications 4.6 Summary 4.7 Appendix References

5 Mining the Cambridge Structural Database for Bioisosteres

5.1 Introduction 5.2 The Cambridge Structural Database 5.3 The Cambridge Structural Database System

5.3.1 ConQuest 5.3.2 Mercury 5.3.3 WebCSD 5.3.4 Knowledge-Based Libraries Derived from the CSD

5.4 The Relevance of the CSD to Drug Discovery 5.5 Assessing Bioisosteres: Conformational Aspects 5.6 Assessing Bioisosteres: Nonbonded Interactions 5.7 Finding Bioisosteres in the CSD: Scaffold Hopping and Fragment Linking

5.7.1 Scaffold Hopping 5.7.2 Fragment Linking

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

5.8.1 Conformational Mimicry 5.8.2 Intermolecular Interactions

5.9 Conclusions References

6 Mining for Context-Sensitive Bioisosteric Replacements in Large Chemical Databases

6.1 Introduction 6.2 Definitions 6.3 Background 6.4 Materials and Methods

6.4.1 Human Microsomal Metabolic Stability 6.4.2 Data Preprocessing 6.4.3 Generation of Matched Molecular Pairs 6.4.4 Context Descriptors

6.4.4.1 Whole Molecule Descriptors 6.4.4.2 Local Environment Descriptors

6.4.5 Binning of DP Values 6.4.6 Charts and Statistics

6.5 Results and Discussion

6.5.1 General Considerations

6.6 Conclusions References

Part Three: Methods

7 Physicochemical Properties

7.1 Introduction 7.2 Methods to Identify Bioisosteric Analogues 7.3 Descriptors to Characterize Properties of Substituents and Spacers 7.4 Classical Methods for Navigation in the Substituent Space 7.5 Tools to Identify Bioisosteric Groups Based on Similarity in Their Properties 7.6 Conclusions References

8 Molecular Topology

8.1 Introduction 8.2 Controlled Fuzziness 8.3 Graph Theory 8.4 Data Mining

8.4.1 Graph Matching 8.4.2 Fragmentation Methods

8.5 Topological Pharmacophores 8.6 Reduced Graphs 8.7 Summary References

9 Molecular Shape

9.1 Methods

9.1.1 Superposition-Based Shape Similarity Methods 9.1.2 Superposition-Free Shape Similarity Methods 9.1.3 Choosing a Shape Similarity Technique for a Particular Project

9.2 Applications 9.3 Future Prospects References

10 Protein Structure

10.1 Introduction 10.2 Database of Ligand–Protein Complexes

10.2.1 Extraction of Ligands 10.2.2 Assessment of Ligand and Protein Criteria 10.2.3 Cavity Generation 10.2.4 Generation and Validation of SMILES String 10.2.5 Generation of FASTA Sequence Files 10.2.6 Identification of Intermolecular Interactions

10.3 Generation of Ideas for Bioisosteres

10.3.1 Substructure Search 10.3.2 Sequence Search 10.3.3 Binding Pocket Superposition 10.3.4 Bioisostere Identification

10.4 Context-Specific Bioisostere Generation 10.5 Using Structure to Understand Common Bioisosteric Replacements 10.6 Conclusions References

Part Four: Applications

11 The Drug Guru Project

11.1 Introduction 11.2 Implementation of Drug Guru 11.3 Bioisosteres 11.4 Application of Drug Guru 11.5 Quantitative Assessment of Drug Guru Transformations 11.6 Related Work 11.7 Summary: The Abbott Experience with the Drug Guru Project References

12 Bioisosteres of an NPY-Y5 Antagonist

12.1 Introduction 12.2 Background 12.3 Potential Bioisostere Approaches 12.4 Template Molecule Preparation 12.5 Database Molecule Preparation 12.6 Alignment and Scoring 12.7 Results and Monomer Selection 12.8 Synthesis and Screening 12.9 Discussion 12.10 SAR and Developability Optimization 12.11 Summary and Conclusion References

13 Perspectives from Medicinal Chemistry

13.1 Introduction 13.2 Pragmatic Bioisostere Replacement in Medicinal Chemistry: A Software Maker.s Viewpoint 13.3 The Role of Quantum Chemistry in Bioisostere Prediction 13.4 Learn from ‘‘Naturally Drug-Like’’ Compounds 13.5 Bioisosterism at the University of Sheffield References

Index

← Prev
Back
Next →

← Prev
Back
Next →