Structure-Based Drug Discovery: An Overview (RSC Biomolecular Sciences, Volume 3)

Hubbard, Roderick E

ISBN 10: 0854043519 / ISBN 13: 9780854043514

Verlag: Royal Society of Chemistry, 2006

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Bibliografische Details

• Titel: Structure-Based Drug Discovery: An Overview (RSC Biomolecular Sciences, Volume 3)
• Verlag: Royal Society of Chemistry
• Erscheinungsjahr: 2006
• Sprache: Englisch
• ISBN-10: 0854043519
• ISBN-13: 9780854043514
• Einband: Hardcover
• Zustand: new

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Inhaltsangabe

Structure-based drug discovery is a collection of methods that exploits the ability to determine and analyse the three dimensional structure of biological molecules. These methods have been adopted and enhanced to improve the speed and quality of discovery of new drug candidates. After an introductory overview of the principles and application of structure-based methods in drug discovery, this book then describes the essential features of the various methods. Chapters on X-ray crystallography, NMR spectroscopy, and computational chemistry and molecular modelling describe how these particular techniques have been enhanced to support rational drug discovery, with discussions on developments such as high throughput structure determination, probing protein-ligand interactions by NMR spectroscopy, virtual screening and fragment-based drug discovery. The concluding chapters complement the overview of methods by presenting case histories to demonstrate the major impact that structure-based methods have had on discovering drug molecules. Written by international experts from industry and academia, this comprehensive introduction to the methods and practice of structure-based drug discovery not only illustrates leading-edge science but also provides the scientific background for the non-expert reader. The book provides a balanced appraisal of what structure-based methods can and cannot contribute to drug discovery. It will appeal to industrial and academic researchers in pharmaceutical sciences, medicinal chemistry and chemical biology, as well as providing an insight into the field for recent graduates in the biomolecular sciences.

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Structure-Based Drug Discovery an Overview

By Roderick E. Hubbard

The Royal Society of Chemistry

Copyright © 2006 The Royal Society of Chemistry
All rights reserved.

ISBN: 978-0-85404-351-4

Contents

Chapter 1 3D Structure and the Drug Discovery Process Roderick E. Hubbard, 1, 
Chapter 2 Structure Determination – Crystallography for Structure-Based Drug Discovery David G. Brown and Maria M. Flocco, 32, 
Chapter 3 Molecular Modelling Xavier Barril and Robert Soliva, 54, 
Chapter 4 Applicatiions of NMR in Structure-Base Drug Discovery Ben Davis and Julia Hubbard, 97, 
Chapter 5 Fragment Screening: An Introduction Andrew R. Leach, Michael M. Hann, Jeremy N. Burrows and Ed Griffen, 142, 
Chapter 6 Iterative Structure-Based Screening of Virtual Chemical Libraries and Factor Xa: Finding the Orally Available Antithrombotic Candidate LY517717 John W. Liebeschuetz, Stuart D. Jones, Michael R. Wiley and Steven C. Young, 173, 
Chapter 7 Anti-Influenza Drugs from Neuraminidase Inhibitors Peter Colman, 193, 
Chapter 8 Isoform Specificity: The Design of Estrogen Receptor-βSelective Compounds Eric S. Manas, Richard E. Mewshaw, Heather A. Harris, and Michael S. Malamas, 219, 
Subject Index, 257, 

CHAPTER 1

3D Structure and the Drug Discovery Process

RODERICK E. HUBBARD

Vernalis (R&D) Ltd, Granta Park, Abington, Cambridge CB1 6GB, UK and University of York, Structural Biology Lab, York, YO10 5YW, UK

1 Introduction

The past 30 years has seen an accelerating increase in our understanding of the molecular mechanisms that underlie disease processes. This has had a fundamental impact on the process of drug discovery, and most of modern pharmaceutical research is based on target-focused discovery, where the goal is to affect the biological activity of a particular molecular target to provide a cure or treatment for a disease. As the 3D structures of some of these targets have become available, a range of experimental and computational methods have been developed to exploit that structure in drug discovery. These developments and some of their applications are the subject of this book.

In a target-focused approach, the cycle of discovery is very similar with or without a structure for the target. Initial-hit compounds are found that bind to the target and enter a medicinal chemistry cycle of making compound analogues and testing in suitable biological models. From this, the chemist builds hypotheses of what is important for the activity. Using experience (or inspired guesses) the chemist then makes changes that should improve the properties of the compound and the cycle of synthesis, testing and design begins again. These hypotheses develop a model of the conformations the compounds adopt, the chemical surfaces they project and the interactions made with the active site. For example, the optimisation of sildenafil (Viagra), included consideration of the electronic properties of an initial-hit compound and how it could be improved to more closely mimic the known substrate in the active site of phosphodiesterase, many years before the structure of this enzyme was known.

Nowadays an appreciation of the 3D structure of both the compounds and their target are a part of just about every drug-discovery project. This target structure can be experimentally determined, a model constructed on the basis of homology or a virtual model of the receptor created on the basis of the chemical structure of the known active compounds. In addition, computational methods such as virtual screening and experimental methods such as fragment screening can generate many new ideas for compound templates and possible interactions with the active site. The major advantage of experimentally determining the structure of these different compounds bound to the target is to increase the confidence in the hypotheses and increase the scope of subsequent design. This encourages the medicinal chemists to embark on novel and often challenging syntheses in the search for novel, distinctive and drug-like lead compounds. Our ability to predict conformational changes in proteins and the binding energy of protein-ligand complexes remains relatively poor, so there is still plenty of scope for experience, inspiration and guess work in the details of design.

This book will provide an overview of the methods currently used in structure-based drug discovery and give some insights into their application. Essentially, all of the examples and methods focus on proteins as the therapeutic target. There has been considerable progress in the structural biology of RNA and DNA molecules and these classes of molecules are the recognised target for some successful drugs. For DNA, our understanding of the binding of compounds that intercalate or bind to the small groove is reasonably well advanced (for an early example, see Henry; current perspectives are provided in Tse and Boger, and Neidle and Thurston,). There have also been spectacular advances in determining the structure of whole ribosome sub-units and of representative portions of the ribosomal RNA in complex with known natural product antibiotics. These structures have led to some hope that rational structure-based methods may be applied against the ribosome and also other RNA targets where a particular conformation has a role in disease processes (Knowles et al., 2002). Although there has been some progress and it has been possible to discover compounds with reasonable affinity for RNA, there remain considerable difficulties in designing small, drug-like molecules with the required specificity to discriminate between the very similar sites presented on RNA. For these reasons, the discussions in this book focus on proteins as the therapeutic target.

2 The Drug Discovery Process

As discussed in the Preface, drug discovery is an expensive and time-consuming activity that mostly fails. Retrospective analyses of the pharmaceutical industry during the 1990s estimate that each new drug in the market takes an average 14 years to develop, costing in the region of $800 million. In addition one in nine compounds that enters clinical trials makes it to the market. The attrition rate in discovery research is similarly high. Depending on the company, therapeutic area and discovery strategy, at best only one in ten research projects that begin with a starting compound will generate an optimised candidate to enter clinical trials. For these reasons, most companies maintain a pipeline with a large number of projects in the early stages, taking a diminishing number forward at each stage. The discovery process gets more expensive as you proceed, hence careful management of the portfolio is essential. The key is to make the right decision at the right time – knowing when to stop a project is often more important than committing to continuing.

Modern, target-oriented drug discovery is usually organised into a series of stages. The definitions of these stages differ from company to company and the details of the boundaries will vary from project to project. The following discussion provides an illustration of the stages, their purpose and duration and the types of resources involved. Clear criteria need to be established for moving from one stage to another as, in general, the stages become progressively more resource and expense intensive (Figure 1).

2.1 Establishing a Target

Clearly, the starting point for a target-oriented drug-discovery project is to identify a relevant target. In the pre-genomic era, targets were discovered...