Bioisosteres in Medicinal Chemistry

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Derrick Miller
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1 Edited by Nathan Brown Bioisosteres in Medicinal Chemistry VCH Verlag GmbH & Co. KGaA

2 Contents List of Contributors Preface XV A Personal Foreword XI XVII Part One Principles 1 Bioisosterism in Medicinal Chemistry 3 Nathan Brown 1.1 Introduction Isosterism Bioisosterism Bioisosterism in Lead Optimization Common Replacements in Medicinal Chemistry Structure-Based Drug Design Optimization Conclusions 13 References 14 2 Classical Bioisosteres 15 Caterina Barillari and Nathan Brown 2.1 Introduction Historical Background Classical Bioisosteres Monovalent Atoms and Groups Bivalent Atoms and Groups Trivalent Atoms and Groups 18 Tetravalent Atoms Ring Equivalents Nonclassical Bioisosteres Carbonyl Group Carboxylic Acid Hydroxyl Group Catechol 22

3 VI Contents Halogens Amide and Esters Thiourea Pyridine Cyclic Versus Noncyclic Systems Summary 27 References 27 3 Consequences of Bioisosteric Replacement Dennis A. Smith and David S. Millan 3.1 Introduction Bioisosteric Groupings to Improve Permeability Bioisosteric Groupings to Lower Intrinsic Clearance Bioisosteric Groupings to Improve Target Potency Conclusions and Future Perspectives 47 References 49 Part Two Data 53 4 BIOSTER: A Database of Bioisosteres and Bioanalogues 55 and Julian Introduction Historical Overview and the Development of BIOSTER Representation of Chemical Transformations for Reaction Databases The Concept of "Biosteric Transformation" Other Analogue and Bioisostere Databases Description of BIOSTER Database Coverage and Selection Criteria Sources Description of the Layout of Database Records ID Code Biosteric Transformation Citation(s) Activity Fragments Component Molecules and Fragments Examples Benzodioxole Bioisosteres Phenol Bioisosteres Applications Summary Appendix 70 References 71

4 Contents VII 5 Mining the Cambridge Structural Database for Bioisosteres 75 Colin R. Groom, Tjelvar S. G. John W. David A. Bardwell, J. Bruno, and Frank Allen 5.1 Introduction The Cambridge Structural Database The Cambridge Structural Database System ConQuest Mercury WebCSD Knowledge-Based Libraries Derived from the CSD The Relevance of the CSD to Drug Discovery Assessing Bioisosteres: Conformational Aspects Assessing Bioisosteres: Nonbonded Interactions Finding Bioisosteres in the CSD: Scaffold Hopping and Fragment Linking Scaffold Hopping Fragment Linking A Case Bioisosterism of 1 and Carboxylic Acid Groups Conformational Mimicry Intermolecular Interactions 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 6.1 Introduction Definitions Background Materials and Methods Human Microsomal Metabolic Stability Data Preprocessing Generation of Matched Molecular Pairs Context Descriptors Whole Molecule Descriptors Local Environment Descriptors Binning of AP Values Charts and Statistics Results and Discussion General Considerations J Conclusions 124 References 125

5 VIII Contents Part Three Methods Physicochemical Properties 131 Peter 7.1 Introduction Methods to Identify Bioisosteric Analogues Descriptors to Characterize Properties of Substituents and Spacers Classical Methods for Navigation in the Substituent Space Tools to Identify Bioisosteric Groups Based on Similarity in Their Properties Conclusions 138 References Molecular Topology 141 Nathan Brown 8.1 Introduction Controlled Fuzziness Graph Theory Data Mining Graph Matching Fragmentation Methods Topological Pharmacophores Reduced Graphs Summary 151 References 9 Molecular Shape 155 Pedro J. Ballester and Nathan Brown 9.1 Methods Superposition-Based Shape Similarity Methods Shape Similarity Methods Choosing a Shape Similarity Technique for a Particular Project Applications Future Prospects 164 References 165 Protein Structure 167 James E.J. Mills 10.1 Introduction Database of Complexes Extraction of Ligands Assessment of Ligand and Protein Criteria 169

6 Contents IX Generation and Validation of SMILES String of FASTA Sequence Files Identification of Interactions of Ideas for Bioisosteres Search Search pocket Superposition Identification Context-Specific Bioisostere Generation Using to Understand Common Bioisosteric Conclusions 180 References 180 Part Four Applications 183 Drug Project 185 Jason B. Alsayyed Ahmed, Bowen 11.1 Introduction of Drug Guru of Drug Guru 11.5 Assessment of Drug Guru Transformations 11.6 Abbott Experience with the Drug Project 197 References 198 of an Antagonist 199 Nicholas Barton and Benjamin R Background Bioisostere Approaches 201 Molecule Preparation Molecule Preparation and Scoring Results Monomer Selection Synthesis and Screening Pevelopability Optimization and Conclusion 214 References 214

7 X Contents 13 Perspectives from Medicinal Chemistry 217 Nicholas A. Meanwell, Marcus Gastreich, Matthias Rarey, Mike Devereux, Paul LA. Popelier, Gisbert Schneider, and Peter Willett 13.1 Introduction Pragmatic Bioisostere Replacement in Medicinal Chemistry: A Software Maker's Viewpoint The Role of Quantum Chemistry in Bioisostere Prediction Learn from "Naturally Drug-Like" Compounds 223 Bioisosterism at the University of Sheffield 224 References 227 Index 231

CSD. Unlock value from crystal structure information in the CSD

CSD. Unlock value from crystal structure information in the CSD CSD CSD-System Unlock value from crystal structure information in the CSD The Cambridge Structural Database (CSD) is the world s most comprehensive and up-todate knowledge base of crystal structure data,