Molecular Modelling and Drug Design Topics in Molecular and Structural Biology

MOLECULAR MODELLING AND DRUG DESIGN TOPICS IN MOLECULAR AND STRUCTURAL BIOLOGY

Series Editors:

Stephen Neidle Institute of Cancer Research Sutton, Surrey, UK

Watson Fuller Department of Physics University of Keele, UK

Jack S. Cohen Georgetown University, USA

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MOLECULAR MODELLING AND DRUG DESIGN

Edited by

J.G. VINTER AND MARK GARDNER

M MACMILLAN © J. G. Vinter and M. Gardner 1994 Softcover reprint of the hardcover 1st edition 1994 978-0-333-57810-0

All rights reserved. No reproduction, copy or transmission of this publication may be made without written permission.

No paragraph of this publication may be reproduced, copied or transmitted save with written permission or in accordance with the provisions of the Copyright, Designs and Patents Act 1988, or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 9HE.

Any person who does any unauthorized act in relation to this publication may be liable to criminal prosecution and civil claims for damages.

First published 1994 by THE MACMILLAN PRESS LTD Houndmills, Basingstoke, Hampshire RG21 2XS and London Companies and representatives throughout the world

ISBN 978-1-349-12975-1 ISBN 978-1-349-12973-7 (eBook) DOI 10.1007/978-1-349-12973-7 ISSN 0265-4377

A catalogue record for this book is available from the British Library Contents

Preface ix

The Contributors XI 1. Molecular modelling methods W. A. Wylie 1 1. Introduction 1 2. Molecular orbital (MO) theory 2 3. Empirical methods 14 4. Geometry optimization techniques 27 5. Atomic point charge calculation 30 6. Exploring conformational space 39 7. Free energy perturbation (FEP) 44

2. Molecular mechanics: Problems and potential 1. M. Goodman 53 1. Introduction 53 2. Molecular orbital calculations 54 3. Molecular mechanics 60 4. Simple models of electrostatics 64 5. Point charges 67 6. Solvents 73 7. Modelling reactivity 75 8. The problem of too many answers 83 9. Conclusions 84

3. The global minimum problem in molecular mechanics: Simulated annealing and related techniques S. D. Morley 89 1. Introduction 89 2. Conformational space-searching algorithms 90 3. Simulated annealing 101

v vi Contents

4. Modelling of multimolecular systems 106 5. The dynamic Monte Carlo (DMC) simulation algorithm 107 6. The conformation of an antigenic peptide fragment of human polymorphic epithelial mucin 112 7. Docking simulations of host-guest complexes 119 8. Conclusions 130

4. The Castlemaine Project: Development of an AI·based drug design support system E. E. Hodgkin 137 1. Introduction 137 2. The Castle maine model of drug design 139 3. The role of AI techniques in the Castle maine project 162 4. Drug design or drug discovery? 165 5. Conclusion 167

5. A discussion of various computational methods for drug design R. Lewis and E. Meng 170 1. Introduction 170 2. Methods 179 3. Case studies 203 4. Conclusion 206

6. Applications of artificial intelligence in molecular modelling and drug design A. R. Leach 211 1. Introduction 211 2. Search 214 3. Expert systems 222 4. The representation of knowledge 223 5. Computer languages for AI applications 224 6. The 'classic' applications of AI in chemistry: Mass spectrometry and organic synthesis 226 7. The application of AI to conformational analysis 227 8. Database applications related to AI 246 9. QSAR 247 10. Rule induction 251 11. Neural networks 254 12. Molecule design 258 13. Conclusions 260

7. The calculation, representation and analysis of molecular fields P. W. Finn 266 1. Introduction 266 2. Electrostatic potential 270 Contents vii

3. Electric field 282 4. Steric fields 283 5. Combined electrostatic and steric fields 284 6. Other fields 289 7. Comparison of molecular fields 291 8. Recent developments and future trends 299

8. Molecular similarity calculations for the rational design of bioactive materials C. Burt 305 1. The drug discovery process 305 2. Molecular similarity 307 3. The application of molecular similarity calculations 317

9. Multivariate QSAR and computational chemistry: A novel receptor model of the Dl agonist binding site D. Manallack 333 1. Introduction 333 2. Methods 342 3. Results 347 4. Discussion 359

10. A perspective of peptide modelling H. Broughton 377 1. Introduction 377 2. The smallest peptides 378 3. Larger peptides 388 4. The problem of conformational space 389 5. Property calculation 411 6. Conclusion 413

11. The developer's perspective - What can be achieved in hardware and software M. Saunders 417 1. Introduction 417 2. Historical note 418 3. Electronic structure calculations 419 4. Molecular mechanics 423 5. Appropriate statistical methods for QSAR studies 427 6. Neural networks 431

Subject Index 439

Index of Program Names 443 Preface

Molecular modelling has developed over the last twenty years largely under the influence of a few pioneers. Lately, as computer technology has become cost-effective, a new young breed of modellers has emerged, bringing with it fresh ideas and energetic approaches. However, we still see the 'old guard' making up the proportion of contributors to compendia on modelling. As such, it is often difficult to find texts which cover the newer aspects of everyday modelling. In this book, we have attempted to collect together some of the best young talents, with a mandate to report without restriction on what interests them. As expected, the resulting collection of broad topics and fresh thinking provides the reader with a taste of the future in drug design and, we hope, the encouragement to break from the old traditions and probe hitherto unexplored avenues of the modelling tool. The contributions cover a broad range of topics from artificial intelli• gence to peptide mimics. There should be something to interest everyone who is involved with the exploration of the interaction of molecules. Because of the freedom of style and subject matter afforded to the contri• butors, it was felt necessary to open the volume with a usefully comprehen• sive overview of the current methods and terminology of modelling. Wil• liam Wyllie has met this requirement in full, intending it to be a reference chapter for those who need to remind themselves of certain aspects or who are new to modelling techniques and jargon. Jonathan Goodman has provided a highly readable introduction which should be the first port of call for those less interested in computational techniques, and David Morley describes the science (and art) of conforma• tional searching and the simulation of host-guest interactions (model re• ceptors?). The reader will then be equipped to launch into the many diverse contributions which make up this book. Andrew Leach comprehensively introduces us to AI in chemistry and Edward Hodgkin puts it into practical perspective. Richard Lewis and Elaine Meng discuss the considerations and approaches to drug design which are expanded and exemplified in the articles by Paul Finn, David

ix x Preface

Manallack and Kate Burt. Paul reports on the exciting use of field analysis which has proved so successful in recent times. David describes in detail the generation of a pharmacophore and introduces the use of QSAR in combination with atomistic modelling, and Kate handles the important problem of molecular similarity and its importance in drug design. Finally, Howard Broughton enthusiastically tackles the particularly difficult but vital area of peptide modelling. To end the book, Martin Saunders gives us both the good news and the bad news from his viewpoint as a chemical software developer, providing balance and caution to an exciting and expanding subject whose expecta• tions are sometimes overestimated by those who are less informed. We would like to thank all the contributors for their encouragement and conscientiousness in putting this volume together. Their views and ideas are an important pointer to future trends in computer-aided drug design which, we can confidently predict, will continue to expand its horizons and play an increasingly important role in the increasingly difficult job of drug discovery.

September, 1993 J.G.V. J.M.F.G. The Contributors

Dr Howard Broughton Dr Richard Lewis Terlings Park Rhone-Poulenc Rorer Eastwick Road Rainham Road South Harlow Dagenham Essex Essex RMlO 7XS CM202QR Dr David ManaUack Dr Kate Burt SmithKline Beecham Formerly: Oxford Molecular The Fry the The Magdalen Centre Welwyn, Herts Oxford Science Park AL69AR Sandford-on-Thames Oxford Dr Elaine Meng OX44GA Department of Pharmaceutical Chemistry Dr Paul Finn University of California Pfizer Central Research San Francisco Sandwich California CA 94144-0446 Kent Cfl3 9NJ Dr David Morley Formerly: Department of Dr Jonathan Goodman Pharmacological Sciences University Chemistry Laboratory University of Nottingham Lensfield Road Nottingham Cambridge NG72RD CB2IEW Dr Martin Saunders Dr Edward Hodgkin SmithKline Beecham British Biotechnology Ltd The Fry the Watlington Road Welwyn, Herts Cowley AL69AR Oxford OX4 5L Y Dr William Wylie Dr Andrew Leach Proteus Molecular Design Ltd Department of Chemistry Proteus House University of Southampton Lyme Green Business Park Highfield Macclesfield Southampton Cheshire S095NH SKll OJL

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