MOLECULAR DIVERSITY IN DRUG DESIGN

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1 MOLECULAR DIVERSITY IN DRUG DESIGN

2 MOLECULAR DIVERSITY IN DRUG DESIGN Edited by PHILIP M. DEAN and RICHARD A. LEWIS KLUWER ACADEMIC PUBLISHERS NEW YORK / BOSTON / DORDRECHT / LONDON / MOSCOW

3 ebook ISBN: Print ISBN: Kluwer Academic Publishers New York, Boston, Dordrecht, London, Moscow All rights reserved No part of this ebook may be reproduced or transmitted in any form or by any means, electronic, mechanical, recording, or otherwise, without written consent from the Publisher Created in the United States of America Visit Kluwer Online at: and Kluwer's ebookstore at:

4 Contents Contributors Acknowledgements Preface Issues in Molecular Diversity and the Role of Ligand Binding Sites JAMES SMITH, PHILIP M. DEAN AND RICHARD A. LEWIS vii xi xiii 1 Molecular Diversity in Drug Design. Application to High-speed Synthesis and High-Throughput Screening 23 CHRISTOPHER G. NEWTON Background Theory of Molecular Diversity 43 VALERIE J. GILLET Absolute vs Relative Similarity and Diversity 67 JONATHAN S. MASON Diversity in Very Large Libraries 93 LUTZ WEBER AND MICHAEL ALMSTETTER Subset-Selection Methods For Chemical Databases 115 P. WILLETT v

5 vi Contents Molecular Diversity in Site-focused Libraries 141 DIANA C. ROE Managing Combinatorial Chemistry Information 175 KEITH DAVIES AND CATHERINE WHITE Design of Small Libraries for Lead Exploration 197 PER M ANDERSON, ANNA LINUSSON, SVANTE WOLD, MICHAEL SJÖSTRÖM, TORBJÖRN LUNDSTEDT AND Bo NORDÉN The Design of Small- and Medium-sized Focused Combinatorial Libraries RICHARD A. LEWIS 221 Index 249

6 Contributors Michael Almstetter Morphochem AG, Am Klopferspitz 19, Martinsried, Germany Per M. Anderson Research Group for Chemometrics Department of Organic Chemistry, Institute of Chemistry, Umeå University, SE Umeå, Sweden Keith Davies Department of Chemistry University of Oxford, UK Philip M. Dean Drug Design Group Department of Pharmacology University of Cambridge, UK Valerie J. Gillet University of Sheffield Western Bank Sheffield S10 2TN, United Kingdom vii

7 viii Issues in Molecular Diversity and the Role of Ligand Binding Sites Richard A. Lewis Eli Lilly & Co. Ltd Lilly Research Centre Windlesham Surrey GU20 6PH UK Anna Linusson Research Group for Chemometrics Department of Organic Chemistry, Institute of Chemistry, Umeå University, SE Umeå, Sweden Torbjörn Lundstedt Structure Property Optimization Center, Pharmacia & Upjohn AB, SE Uppsala, Sweden Jonathan S. Mason Bristol-Myers Squibb PO Box 4000 Princeton NJ08543 USA Christopher G. Newton Dagenham Research Centre Rhone-Poulenc Rorer Rainham Road South Dagenham, Essex RM 10 7XS UK Bo Nordén Medicinal Chemistry, Astra Hassle AB, SE Mölndal, Sweden Diana C. Roe Sandia National Labs, Mail Stop 9214, P.O. Box 969, Livermore, CA USA Michael Sjöström Research Group for Chemometrics, Department of Organic Chemistry, Institute of Chemistry, Umeå University, SE Umeå, Sweden

8 Issues in Molecular Diversity and the Role of Ligand Binding Sites ix James Smith Drug Design Group Department of Pharmacology, University of Cambridge, UK Svante Wold Research Group for Chemometrics, Department of Organic Chemistry, Institute of Chemistry, Umeå University, SE Umeå, Sweden Lutz Weber Morphochem AG, Am Klopferspitz 19, Martinsried, Germany Peter Willett Department of Information Studies, University of Sheffield, Western Bank, Sheffield S10 2TN, UK. Catherine White Oxford Molecular Group, Oxford, UK

9 Acknowledgements P.M.D. would like to acknowledge the Wellcome Trust for encouragement and financial support provided over many years; Rhone- Poulenc Rorer have also contributed significant laboratory funding. R.A.L. would like to thank Ann-Marie O Neill for her patience, and the management at Eli Lilly and Rhone-Poulenc Rorer for providing environments that allowed scientific debate to flourish. We are grateful to Peter Butler, Janet Hoffman and the staff of Kluwer for their help in producing this book; any errors that remain are solely the fault of the editors. xi

10 Preface High-throughput screening and combinatorial chemistry are two of the most potent weapons ever to have been used in the discovery of new drugs. At a stroke, it seems to be possible to synthesise more molecules in a month than have previously been made in the whole of the distinguished history of organic chemistry, Furthermore, all the molecules can be screened in the same short period. However, like any weapons of immense power, these techniques must be used with care, to achieve maximum impact. The costs of implementing and running high-throughput screening and combinatorial chemistry are high, as large dedicated facilities must be built and staffed. In addition, the sheer number of chemical leads generated may overwhelm the lead optimisation teams in a hail of friendly fire. Mother nature has not entirely surrendered, as the number of building blocks that could be used to build libraries would require more atoms than there are in the universe. In addition, the progress made by the Human Genome Project has uncovered many proteins with different functions but related binding sites, creating issues of selectivity. Advances in the new field of pharmacogenomics will produce more of these challenges. There is a real need to make highthroughput screening and combinatorial chemistry into 'smart' weapons, so that their power is not dissipated. That is the challenge for modellers, computational chemists, cheminformaticians and IT experts. In this book, we have broken down this grand challenge into key tasks. In chapter 1, Smith, Dean and Lewis define in detail many of the key issues in molecular diversity and in the analysis of binding sites, showing how subtle changes in sequence can be translated into features that could drive library design. The next chapter by Newton deals with the considerable logistical and managerial challenges of running combinatorial chemistry and. high-throughput screening laboratories, and gives a clear picture of how to xiii

11 xiv Issues in Molecular Diversity and the Role of Ligand Binding Sites obtain the best value from these operations. Chapter 3 by Gillet lays out rigorously the theory underpinning molecular diversity and the design of libraries, followed by a practical demonstration of the theory by Mason in his elegant paper applying 4-centre pharmacophores to the design of privileged libraries. In chapter 5, Weber and Almstetter describe recent advances in methods for dealing with very large libraries, libraries that could never be contemplated without the tools provided by molecular diversity. Again, both the theory and practical examples are given. Next, Willett reviews critically all the current methods for selecting subsets of libraries, providing clear guidance as to the best ways to approach this task. Roe then tackles the particular issue of how to design libraries using the constraints of a protein active site; the prospects offered by the marriage of site-directed drug design and molecular diversity are very exciting. In chapter 8, Davies and White discuss the IT issues created by the large volumes of data that can be created during the design, synthesis and screening of combinatorial libraries. It is very apparent that the ability to store and query large volume of textual, numeric and structural data needs to be seen as the new and required enabling technology if the field is to move forward and realise its promise. Combinatorial libraries can also be small, if the products are expensive or difficult to make. Andersson et al. show how chemometrics can be applied to get the most value out of small libraries, using procedures that will be new to most medicinal chemists. Finally, Lewis discusses how to design small and medium-sized libraries to optimise SARs; this is in recognition of the fact that the techniques of combinatorial chemistry are increasingly being used by medicinal chemists during lead optimisation. Each chapter conveys, we hope, how exciting and intellectually challenging the field of molecular diversity in drug design is. We expect the next five years to generate even more advances, to modify the scatterguns of highthroughput screening and combinatorial chemistry into weapons more capable of firing the elusive magic bullets of potent drugs. Philip Dean Richard Lewis July 1999

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