Brown

Bioisosteres in Medicinal Chem

Herausgegeben von Brown, Nathan; Mannhold, Raimund; Kubinyi, Hugo; Folkers, Gerd

• Gebundenes Buch

Produktbeschreibung

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.

Produktdetails

• Methods and Principles in Medicinal Chemistry Vol.54
• Verlag: Wiley-VCH
• Artikelnr. des Verlages: 1133015 000
• 1. Auflage
• Seitenzahl: 256
• Erscheinungstermin: 22. August 2012
• Englisch
• Abmessung: 250mm x 175mm x 18mm
• Gewicht: 640g
• ISBN-13: 9783527330157
• ISBN-10: 3527330151
• Artikelnr.: 34821496

Autorenporträt

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.

Inhaltsangabe

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