Computer-Aided Molecular Design: Theory and Applications

517 Pages·1996·24.77 MB·English

by  Jean-Pierre Doucet

Computer-Aided Molecular Design:
Theory and Applications
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Computer-Aided Molecular Design:
Theory and Applications
Jean-Pierre Doucet
Institut de Topologie et de Dynamique de Systems
Universit~ de Paris 7-Denis Diderot
1 rue Guy de la Brosse
75005 Paris
France
Jacques Weber
D6partemeut de Chimie Physique
Universit~ de Gen~ve
30 quai Ernest-Ansermet
1211 Gen~ve 4
Suisse
Academic Press
Harcourt Brace & Company, Publishers
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ACADEMIC PRESS LIMITED
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U.S. Edition Published by
ACADEMIC PRESS INC.
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This book is printed on acid free paper
Copyright (cid:14)9 1996
ACADEMIC PRESS LIMITED
Second Printing 1997
All rights reserved
No part of this book may be reproduced or transmitted in any form or by any
means, electronic or mechanical including photocopying, recording, or any
information storage and retrieval system without permission in writing from the
publisher.
A catalogue record for this book is available from the British Library
ISBN 0-12-221285-1
Typeset by Phoenix Photosetting, Chatham, Kent UK
Printed and bound in Great Britain by Hartnolls Limited, Bodmin, Cornwall
Contents
Preface vii
Acknowledgements ix
Introduction xvii
1 Computer graphics: an introduction 1
1.1 Display and input devices 2
1.2 Elementary graphics primitives 9
1.3 Geometrical transformations 17
2 Computer graphics: towards realistic images 23
2.1 Representation of 3D objects 24
2.2 Viewing, windowing and clipping 31
2.3 Segments 37
2.4 Hidden lines and surfaces removal 38
2.5 Rendering 49
3 Displaying molecular shapes 59
3.1 Representation of structural shapes 61
3.2 Representation of property shapes 70
3.3 Concluding remarks: symbolic pictorial primitives 78
4 Access to experimental geometrical parameters 81
4.1 Crystals and X-ray diffraction 82
4.2 Neutron scattering and miscellaneous techniques 89
4.3 NMR: a source of geometrical data in solution 92
4.4 The Cambridge Structural Database 103
4.5 The Brookhaven Protein Data Bank 118
4.6 Databases of calculated structures 120
5 Empirical force field methods and molecular mechanics 124
5.1 The force field 127
5.2 Steric energy and derived information: strain energy and heat of formation 139
5.3 Search for the preferred geometry and energy minimization 140
5.4 Molecular mechanics: scope, limitations and evolution 144
5.5 Some applications 151
5.6 Trends and prospects 165
6 Monte Carlo and molecular dynamics simulations 171
6.1 Monte Carlo simulations 172
6.2 Molecular dynamics simulations 183
Exploring the conformational space: distance geometry
and model builders 197
7.1 Distance geometry 2O0
7.2 Exploring the conformational space 206
7.3 Model builders 220
vi CONTENTS
8 Molecular surfaces and volumes 239
8.1 Definition of molecular volumes 240
8.2 Analytical evaluations of surfaces or volumes 243
8.3 Numerical methods 247
8.4 Boolean operations and molecular comparisons 256
8.5 Towards quantitative relationships 257
8.6 Concluding remarks: roughness and fractal surfaces 261
Key features of quantum chemistry methods used
in CAMD 266
9.1 The time-independent Schr6dinger equation 269
9.2 Hartree-Fock and Roothaan equations: AB initio methods 273
9.3 Semi-empirical methods 282
9.4 Density functional methods 293
10 Derivation and visualization of molecular properties 301
10.1 Molecular orbitals 301
10.2 Electron densities 308
10.3 Electrostatic properties 311
10.4 Reactivity indices 319
11 Molecular similarity 328
11.1 Geometrical comparisons: molecular superimposition 332
11.2 Common substructure searches 340
11.3 Similarity between structural shapes 352
12 Drug receptor interactions: receptor mapping and pharmacophore
approach 363
12.1 The pharmacophore hypothesis 364
12.2 Active conformations of a drug: feasible binding modes of a ligand
molecule at the receptor site 367
13 Modelling proteins 405
13.1 Structural analysis 408
13.2 Representation 411
13.3 Determination of geometrical data: 2D NMR in protein structural analysis 415
13.4 Computer building 426
13.5 Knowledge-based prediction: model building from homology 431
13.6 Evaluating similarity 447
Subject index 463
Author index 475
Colour plate section between pages 236 to 237
Preface
The originality of this book is to train undergraduates, who have grown up
during the computer revolution, in the core parts of those computer tools
intended to help chemists, with graphics assistance, in handling molecular
representations. The goal is complex, as there is an important synergy in the
creative design of molecules or properties between the fundamental theories of
chemistry and their computational extensions.
This duality, felt constantly through the last thirty years, has led to
immense progress thanks to major developments in both chemical informatics
and computational chemistry.
The authors, well known actors in this transformation of chemistry, have
identified in a single book the foundations of the modelling and design
successes in chemistry. Their aim is to teach some crucial components both in
the computer field and in theoretical chemistry, often closely linked in
CAMD. The two authors, who have participated in the deployment of CAMD,
have identified and selected, with talent and efficiency, its fundamental
elements. Their teaching is clear with alternate explanations and applications.
The task was not simple, as these elements are shadowed by the progress of the
information revolution and the rapid advances of molecular modelling. The
synergy of these actions often obscures the identification of those basic
components essential for an up to date course.
Thus, Computer Aided Molecular Design (CAMD) is identified as a mature
discipline. The theoretical and practical aspects of its potential and of its basic
tenets are described. Applications are chosen to underline the power of various
CAMD strategies.
There are many reasons for such a course at the undergraduate level.
Students are usually familiar with the information revolution, and they know
that the rapid evolution of science and technology makes it imperative to
acquire generalized training enabling them to deal with many changes in their
active life. They are sensitive to the radical changes around them in
communication fields, and they are aware that equivalent transformations
and mutations are taking place in science and technology. These affect our
vision of science but also modify our working methods both in our chosen
field of activity and in the methods we use. A brief sample enumeration of
such trends helps to justify special training such as CAMD. Let us cite, for
instance: the dramatic improvement expected in data and information
sharing; CAMD collaboration (online or offlinr between researchers and
engineers separated by physical distance; the increase use of visual tools and
methods for viewing, animating, interacting with CAMD mechanisms; the
development of heuristic design through intelligent agents endowed with
browsing capabilities.
For chemists to take advantage of all this, it is essential to point out that
viii PREFACE
chemistry is based on numerous concepts conferring more or less precise 2D or
3D shapes on 'invisible' molecules.
The imaginary world of chemistry is thus geometrical, shape oriented and
thereby open to graphics. Molecular species lead to either property maps or
volumes incorporating all information derived from the molecular paradigm.
Graphics presentations are used to handle the conceptual nature of bonds, the
conformational flexibility of entities and chemical transformations.
This knowledge will be necessary for the future chemist if he is to make free
use of modern tools.
J. P. Doucet and J. Weber have woven together the powerful tools of
classification and correlation that help conduct similarity searches. Here the
basic blocks are those derived from fragmentation or topological procedures.
They are used to build adequate working 'spaces of states' suited to correlation
searches.
Molecular similarity is presented in a drug design application to illustrate
the complexity involved in the search of a 'lead' drug and the difficulties
encountered in estimating the embedding of a drug on a biological receptor.
The book maintains its homogeneity on structural design, but its authors
successfully tackle CAMD tools and applications in bioinformatics.
In short, this book presents an excellent package of complementary ideas
and tools and should greatly help students to master their use of molecular
software. Instead of blindly applying programs, their knowledge of CAMD will
give them the freedom required in creative molecular design research. Finally,
this work should be kept by them as a long term classical reference volume.
Jacques-Emile Dubois
Professor, ITODYS, University Paris 7.
(President of CODATA}
Acknowledgements
The following have kindly granted permission to reprint the illustrations cited.
Scheme on pp. 20-21 From W.M. Newman and R.F. Sproull Principles of Interactive
Computer Graphics. 2e, 1979. McGraw-Hill Inc. Ed, Copyright 1979 McGraw-Hill, reproduced
with permission of McGraw-Hill Inc.
Figure 2.2 Reproduced from K. Kronlof and M. Tamminen The Visual Computer.
1:1985;24-36. Copyright Springer Verlag 1985. By permission of Springer Verlag Gmbh & Co. A
Viewing Pipeline for Discrete Solid Modeling, p. 25.
Figure 2.5 Adapted from W.M. Newman and R.F. Sproull Principles of Interactive Computer
Graphics. 2e, 1979. McGraw-Hill Inc. Ed, Copyright 1979 McGraw-Hill, reproduced with
permission of McGraw-Hill Inc.
Figure 2.6 Adapted from W.M. Newman and R.F. Sproull Principles of Interactive Computer
Graphics. 2e, 1979. McGraw-Hill Inc. Ed, Copyright 1979 McGraw-Hill, reproduced with
permission of McGraw-Hill Inc.
Figure 2.7 Adapted from W.M. Newman and R.F. Sproull Principles of Interactive Computer
Graphics. 2e, 1979. McGraw-Hill Inc. Ed, Copyright 1979 McGraw-Hill, reproduced with
permission of McGraw-Hill Inc.
Figure 2.8 Adapted from W.M. Newman and R.F. Sproull Principles of Interactive Computer
Graphics. 2e, 1979. McGraw-Hill Inc. Ed, Copyright 1979 McGraw-Hill, reproduced with
permission of McGraw-Hill Inc.
Figure 2.11 Reproduced from G. Wyvill and T.L. Kunii The Visual Computer. 1:1985;3-14.
Copyright Springer Verlag 1985. By permission of Springer Verlag Gmbh & Co. A Functional
Model for Constructive Solid Geometry, p. 3.
Figure 2.22 Reproduced from D.F. Rogers Mathematical Elements for Computer Graphics.
French Translation by J.J. Lecoeur, 1988. McGraw-Hill Inc. Ed, Copyright 1938 McGraw-Hill Inc.
reproduced with permission of McGraw-Hill Inc.
Figure 2.26 Adapted from W.M. Newman and R.F. Sproull Principles of Interactive Computer
Graphics. 2e, 1979. McGraw-Hill Inc. Ed, Copyright 1979 McGraw-Hill, reproduced with
permission of McGraw-Hill Inc.
Figure 2.31 Reproduced from D.F. Rogers Mathematical Elements for Computer Graphics.
French Translation by J.J. Lecoeur, 1988. McGraw-Hill Inc. Ed, Copyright 1988 McGraw-Hill Inc.
reproduced with permission of McGraw-Hill Inc.
Figure 2.34 Adapted from W.M. Newman and R.F. Sproull Principles of Interactive Computer
Graphics. 2e, 1979. McGraw-Hill Inc. Ed, Copyright 1979 McGraw-Hill, reproduced with
permission of McGraw-Hill Inc.
Figure 2.35 Adapted from W.M. Newman and R.F. Sproull Principles of Interactive Computer
Graphics. 2e, 1979. McGraw-Hill Inc. Ed, Copyright 1979 McGraw-Hill, reproduced with
permission of McGraw-Hill Inc.
Figure 2.36 Adapted from W.M. Newman and R.F. Sproull Principles of Interactive Computer
Graphics. 2e, 1979. McGraw-Hill Inc. Ed, Copyright 1979 McGraw-Hill, reproduced with
permission of McGraw-Hill Inc.
Figure 3.2 Reprinted with permission from G.M. Smith and P. Gund J. Chem. Inf. Comput.
Sci. 18:1978;207-210. Copyright 1978 American Chemical Society, and Computer-Generated
Space-Filling Molecular Models, p. 208.
Figure 3.5 From L.H. Pearl J. Molecular Graphics. 6:1988;109-111, and Calculating CPK
images on a UNIX workstation, p. 110.
Figure 3.7 From D.S. Goodsell, I. Saira Mian and A.J. Olson J. Molecular Graphics.
7:1989;41-44, and Rendering Volumetric data in Molecular Systems, p. 43.
Figure 3.9 From M. GwiUiam and N. Max J. Molecular Graphics. 7:1989;54-59, and Atoms with
Shadows- an Area-based Algorithm for Cast Shadows on Space-filling Molecular Models, p. 56.