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.
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.
PREFACE PART ONE: Principles BIOISOSTERISM IN MEDICINAL CHEMISTRY Introduction Isosterism Bioisosterism Bioisosterism in Lead Optimization Conclusions CLASSICAL BIOISOSTERES Introduction Historical Background Classical Bioisosteres Nonclassical Bioisosteres Summary CONSEQUENCES OF BIOISOSTERIC REPLACEMENT Introduction Bioisosteric Groupings to Improve Permeability Bioisosteric Groupings to Lower Intrinsic Clearance Bioisosteric Groupings to Improve Target Potency Conclusions and Future Perspectives PART TWO: Data BIOSTER: A DATABASE OF BIOISOSTERES AND BIOANALOGUES Introduction Historical Overview and the Development of BIOSTER Description of BIOSTER Database Examples Applications Summary Appendix MINING THE CAMBRIDGE STRUCTURAL DATABASE FOR BIOISOSTERES Introduction The Cambridge Structural Database The Cambridge Structural Database System 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 A Case Study: Bioisosterism of 1H-Tetrazole and Carboxylic Acid Groups Conclusions MINING FOR CONTEXT-SENSITIVE BIOISOSTERIC REPLACEMENTS IN LARGE CHEMICAL DATABASES Introduction Definitions Background Materials and Methods Results and Discussion Conclusions PART THREE: Methods PHYSICOCHEMICAL PROPERTIES 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 MOLECULAR TOPOLOGY Introduction Controlled Fuzziness Graph Theory Data Mining Topological Pharmacophores Reduced Graphs Summary MOLECULAR SHAPE Methods Applications Future Prospects PROTEIN STRUCTURE Introduction Database of Ligand - Protein Complexes Generation of Ideas for Bioisosteres Context-Specific Bioisostere Generation Using Structure to Understand Common Bioisosteric Replacements Conclusions PART FOUR: Applications THE DRUG GURU PROJECT Introduction Implementation of Drug Guru Bioisosteres Application of Drug Guru Quantitative Assessment of Drug Guru Transformations Related Work Summary: The Abbott Experience with the Drug Guru Project BIOISOSTERES OF AN NPY-Y5 ANTAGONIST Introduction Background Potential Bioisostere Approaches Template Molecule Preparation Database Molecule Preparation Alignment and Scoring Results and Monomer Selection Synthesis and Screening Discussion SAR and Developability Optimization Summary and Conclusion PERSPECTIVES FROM MEDICINAL CHEMISTRY 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 Bioisosterism at the University of Sheffield