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.