Bioisosteres in Medicinal Chemistry

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 CHEMISTRYIntroductionIsosterismBioisosterism Bioisosterism in Lead OptimizationConclusions CLASSICAL BIOISOSTERES Introduction Historical Background Classical Bioisosteres Nonclassical Bioisosteres Summary CONSEQUENCES OF BIOISOSTERIC REPLACEMENT Introduction Bioisosteric Groupings to Improve PermeabilityBioisosteric Groupings to Lower Intrinsic Clearance Bioisosteric Groupings to Improve Target PotencyConclusions and Future Perspectives PART TWO: Data BIOSTER: A DATABASE OF BIOISOSTERES AND BIOANALOGUESIntroduction Historical Overview and the Development of BIOSTER Description of BIOSTER Database Examples ApplicationsSummaryAppendix MINING THE CAMBRIDGE STRUCTURAL DATABASE FOR BIOISOSTERES Introduction The Cambridge Structural DatabaseThe Cambridge Structural Database SystemThe Relevance of the CSD to Drug Discovery Assessing Bioisosteres: Conformational Aspects Assessing Bioisosteres: Nonbonded Interactions Finding Bioisosteres in the CSD: Scaffold Hopping and Fragment LinkingA 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 AnaloguesDescriptors 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 STRUCTUREIntroduction Database of Ligand -Protein Complexes Generation of Ideas for Bioisosteres Context-Specific Bioisostere Generation Using Structure to Understand Common Bioisosteric ReplacementsConclusions PART FOUR: Applications THE DRUG GURU PROJECT Introduction Implementation of Drug Guru Bioisosteres Application of Drug GuruQuantitative Assessment of Drug Guru TransformationsRelated Work Summary: The Abbott Experience with the Drug Guru Project BIOISOSTERES OF AN NPY-Y5 ANTAGONIST Introduction Background Potential Bioisostere Approaches Template Molecule PreparationDatabase 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 ViewpointThe Role of Quantum Chemistry in Bioisostere Prediction Learn from ''Naturally Drug-Like'' Compounds Bioisosterism at the University of Sheffield

“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)