MOLECULAR MODELLING AND DRUG DESIGN

Transcription

1 MOLECULAR MODELLING AND DRUG DESIGN

2 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 Recent titles: Protein - Nucleic Acid Interaction Edited by Wolfram Saenger and Udo Heinemann (1989) Calcified Tissue Edited by David W. L. Hukins (1989) Oligodeoxynucleotides: Antisense Inhibitors of Gene Expression Edited by Jack S. Cohen (1989) Molecular Mechanisms in Muscular Contraction Edited by John M. Squire (1990) Connective Tissue Matrix, Part 2 Edited by David W. L. Hukins (1990) New Techniques of Optical Microscopy and Microspectroscopy Edited by Richard J. Cherry (1990) Molecular Dynamics: Applications in Molecular Biology Edited by Julia M. Goodfellow (1990) Water and Biological Macromolecules Edited by Eric Westhof (1993)

3 Topics in Molecular and Structural Biology MOLECULAR MODELLING AND DRUG DESIGN Edited by J.G. VINTER AND MARK GARDNER M MACMILLAN

4 J. G. Vinter and M. Gardner 1994 Softcover reprint of the hardcover 1st edition 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 ISBN (ebook) DOI / ISSN A catalogue record for this book is available from the British Library

5 Contents Preface The Contributors 1. Molecular modelling methods W. A. Wylie 1 1. Introduction 1 2. Molecular orbital (MO) theory 2 3. Empirical methods Geometry optimization techniques Atomic point charge calculation Exploring conformational space Free energy perturbation (FEP) Molecular mechanics: Problems and potential 1. M. Goodman Introduction Molecular orbital calculations Molecular mechanics Simple models of electrostatics Point charges Solvents Modelling reactivity The problem of too many answers Conclusions The global minimum problem in molecular mechanics: Simulated annealing and related techniques S. D. Morley Introduction Conformational space-searching algorithms Simulated annealing 101 v ix XI

6 vi Contents 4. Modelling of multimolecular systems The dynamic Monte Carlo (DMC) simulation algorithm The conformation of an antigenic peptide fragment of human polymorphic epithelial mucin Docking simulations of host-guest complexes Conclusions The Castlemaine Project: Development of an AI based drug design support system E. E. Hodgkin Introduction The Castle maine model of drug design The role of AI techniques in the Castle maine project Drug design or drug discovery? Conclusion A discussion of various computational methods for drug design R. Lewis and E. Meng Introduction Methods Case studies Conclusion Applications of artificial intelligence in molecular modelling and drug design A. R. Leach Introduction Search Expert systems The representation of knowledge Computer languages for AI applications The 'classic' applications of AI in chemistry: Mass spectrometry and organic synthesis The application of AI to conformational analysis Database applications related to AI QSAR Rule induction Neural networks Molecule design Conclusions The calculation, representation and analysis of molecular fields P. W. Finn Introduction Electrostatic potential 270

7 Contents 3. Electric field 4. Steric fields 5. Combined electrostatic and steric fields 6. Other fields 7. Comparison of molecular fields 8. Recent developments and future trends vii Molecular similarity calculations for the rational design of bioactive materials C. Burt The drug discovery process Molecular similarity The application of molecular similarity calculations Multivariate QSAR and computational chemistry: A novel receptor model of the Dl agonist binding site D. Manallack Introduction Methods Results Discussion A perspective of peptide modelling H. Broughton 1. Introduction 2. The smallest peptides 3. Larger peptides 4. The problem of conformational space 5. Property calculation 6. Conclusion The developer's perspective - What can be achieved in hardware and software M. Saunders Introduction Historical note Electronic structure calculations Molecular mechanics Appropriate statistical methods for QSAR studies Neural networks 431 Subject Index 439 Index of Program Names 443

8 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 intelligence 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 contributors, it was felt necessary to open the volume with a usefully comprehensive overview of the current methods and terminology of modelling. William 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 conformational searching and the simulation of host-guest interactions (model receptors?). 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

9 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 expectations 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.

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