Bioisosteres in Medicinal Chemistry

1. Auflage 2012
ISBN: 978-3-527-33015-7
Verlag: WILEY-VCH

Buch, Englisch, 238 Seiten, Format (B × H): 170 mm x 240 mm, Gewicht: 624 g

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.

Autoren/Hrsg.

Brown, Nathan

Weitere Mitwirkende

Mannhold, Raimund

Kubinyi, Hugo

Folkers, Gerd

Fachgebiete

• Naturwissenschaften Chemie Chemie Allgemein Pharmazeutische Chemie, Medizinische Chemie
• Medizin | Veterinärmedizin Medizin | Public Health | Pharmazie | Zahnmedizin Medizinische Fachgebiete Pharmakologie, Toxikologie
• Naturwissenschaften Chemie Organische Chemie Biochemie
• Medizin | Veterinärmedizin Medizin | Public Health | Pharmazie | Zahnmedizin Vorklinische Medizin: Grundlagenfächer Biochemie (med.)

Inhaltsverzeichnis

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

Über Autor(innen)

Nathan Brown is the Head of the In Silico Medicinal Chemistry group in the Cancer Research UK Cancer Therapeutics Unit at the Institute of Cancer Research in London (UK). At the ICR, Dr. Brown and his group support the entire drug discovery portfolio together with developing new computational methodologies to enhance the drug design work. Nathan Brown conducted his doctoral research in Sheffield with Professor Peter Willett focusing on evolutionary algorithms and graph theory applied to challenges in chemoinformatics.

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.

His work has led to the pioneering work on mulitobjective design in addition to a variety of discoveries and method development in bioisosteric identification and replacement, scaffold hopping, molecular descriptors and statistical modeling. Nathan continues to pursue his research in all aspects of medicinal chemistry.