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
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.
In all, I believe this book is a musthave handbook onbioisosteres. It is highly valuable both as a text book forgraduate students and as a book of reference for the medicinalchemist working in the industry as well as in an academicsetting. (ChemMedChem, 1 July 2013)
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