Applications of Artificial Intelligence for Organic Chemistry: The Dendral Project (McGraw-Hill advanced computer science series)

203 Pages·1980·11.926 MB·English

by  Robert K. Lindsay, etc.

APPLICATIONS OF
ARTIFICIAL
INTELLIGENCE FOR
ORGANIC CHEMISTRY
The DENDRAL Project
Robert K. Lindsay
Research Scientist
University of Michigan
Bruce G. Buchanan
Adjunct Professor of Computer Science
Stanford University
Edward A. Feigenbaum
Professor of Computer Science
Stanford University
Joshua Lederberg
President, The Rockefeller University
Formerly, Professor of Genetics
Stanford University
McGraw-Hill Book Company
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APPLICATIONS OF ARTIFICIAL INTELLIGENCE
FOR ORGANIC CHEMISTRY
The DENDRAL Project
Copyright Q 1980 by McGraw-Hill, Inc. All rights reserved.
Printed in the United States of America. No part of this publication
may be reproduced, stored in a retrieval system, or transmitted, in any
form or by and means, electronic, mechanical, photocopying, recording, or
otherwise, without the prior written permission of the publisher.
1234567890MAMA 89876543210
This book was set in Times Roman by The Total Book/ACS.
Library of Congesa Catalowg in Publication Data
Main entry under title:
Applications of artificial intelligence for organic
chemistry.
(McGraw-Hill advanced computer science series)
Bibliography: p.
Includes index.
1. DENDRAL (Computer programs) 2. Artificial
intelligence-Data processing. 3. Chemistry, Organic-
Data processing I. Lindsay, Robert K. II. Series.
QD255.5.E4A66 547’0028’5425 80-12508
ISBN O-07-037895-9
CONTENTS
Foreword ix
Preface xi
1 Introduction 1
2 The Structure Elucidation Problem of
Organic Chemistry 3
2.1 Introduction 3
2.2 Isomerism 4
2.3 Organic compounds and Nomenclature 5
2.4 Mass Spectrometry 13
2.5 Some Important Refinements of the MS Technique 19
2.6 Other Analytical Methods 24
2.7 Library Search 26
2.8 Summary 27
3 Artificial Intelligence 28
3.1 Introduction 28
3.2 Problem-Solving Methods 30
3.3 DENDRAL 35
3.4 Outline of DENDRAL Programs 39
4 The DENDRAL Generator 40
4.1 Introduction 40
4.2 Overview 41
4.3 Ring Generation 44
4.4 Tree Generation-The Acyclic Generator 48
4.5 The Cyclic Generator 53
4.6 Constraining the Generator: CONGEN 53
vii
viii CONTENTS
5 Heuristic DENDRAL Planning 68
68
5.1 Introduction
69
5.2 The Early Planner and the Planning Rule Generator
70
5.3 MOLION
78
5.4 Empirical Formula
78
5.5 Generalized Break Analysis
85
5.6 Conclusion
6 Heuristic DENDRAL Testing 86
86
6.1 Introduction
87
6.2 Predictor Production System
88
6.3 Graph Structure and Production Representation
100
4.4 Ranking the Candidate Explanations
105
6.5 Summary of Heuristic DENDRAL
7 Meta-DENDRAL 107
107
7.1 Introduction
109
7.2 INTSUM-Data Interpretation and Summary
115
7.3 RULEGENeration
123
1.4 RULEMODification
125
7.5 Summary
8 Results 126
126
8.1 Introduction
127
8.2 The Scope of Structural Isomerism
130
8.3 Acyclic Heuristic DENDRAL
134
8.4 CONGEN Results
135
8.5 Planner Results
143
8.6 Meta-DENDRAL Results
144
8.7 DENDRAL Predictor Results
147
8.8 Design Principles
9 Summary and Conclusions 153
153
9.1 Introduction
153
9.2 Knowledge Engineering
160
9.3 Scientific Discovery
168
9.4 The Prospects for Automatic Science
10 Project Publications 169
References 179
Name Index 187
Subject Index 189
FOREWORD
It is no pure coincidence that an organic chemist rather than a computer specialist is
writing this foreword. In my opinion the most significant aspect of the development of
DENDRAL is that it can be appreciated and used by a community of scholars that en-
compasses a diverse range from mathematics and computer sciences all the way to
chemistry. The former group has been attracted by DENDRAL’s intrinsic interest and
the latter primarily by its applications. As an organic chemist let me emphasize the
applications.
The use of computers as a computational and data acquisition tool is accepted by
most chemists. This use is especially true as an adjunct to instrumentation (for instance
NMR spectrometers, automated x-ray diffractometers, etc.) and to library searcheso r
spectral file examinations. The use of computers in the manipulation of symbolic
rather than numerical inputs is of much more recent origin and until recently has been
ignored, and for psychologically understandable reasons even opposed, by organic
chemists. I emphasize the organic chemical community because together with bio-
chemistry, it encompasses well over half of all practicing chemists and involves the
least amount of sophisticated mathematics.
Symbolic manipulations by computers are in principle important in two areas of
chemistry-synthesis and structure elucidation. It is the former where the use of com-
puters has not been widely accepted because of the fear that thinking man will simply
be reduced to an appendage to a machine. The synthetic che’mistw ishes to be both
architect and building contractor-the former function being the intellectually and
aesthetically more pleasing one-and it is precisely this architectural role that the com-
puter is perceived partially to usurp.
The structural chemist, on the other hand, has always been receptive to aid from
many different areas-notably a variety of instrumental methods; indeed most physical
methods have entered general organic chemical methodology through the structural
chemist’s interests and efforts. It is not surprising, therefore, that computer-aided
structure elucidation has found more favor than computer-aided design of organic
synthesis. While this argument is primarily emotional, there is also a logical one. No
ix
x FOREWORD
synthetic organic chemist claims, or needs to claim, that he or she has thought of all
possible synthetic paths to a given molecule. The structural chemist, on the other hand,
must be able to claim that every possible structure compatible with the available chem-
ical and physical evidence has been considered. It is here that computer-aided structure
elucidation plays an extraordinarily important role, and it is here that DENDRAL has
made it possible for enormous advances to have occurred in a period of less than 10
years.
It is no mere coincidence that scientists from as diverse disciplines as genetics,
computer sciences, and chemistry collaborated in developing DENDRAL as a logical
and practical concept. The numerous applications of DENDRAL and related computer
programs have now been documented in many scientific publications, and putting all
this material, including the historical background, into one single volume constitutes
an important service for scientists from many fields.
Gzrl Djerassi
Professor of Chemistry
Stanford University
PREFACE
Some explanation of the history and authorship of this book is in order. I began writ-
ing this book while on sabbatical leave from the University of Michigan in 1975. I
had chosen to spend that year at Stanford University to learn firsthand about the
DENDRAL Project. My interest derived from a continuing desire to understand what
has been accomplished by the field of artificial intelligence, with which I have long
been associated but toward which I have tried to maintain a critical stance. DENDRAL
is widely claimed to be one of the most notable successeso f this field. I wondered
what generalizable lessons it had to share.
Ed Feigenbaum suggested that I put my efforts, and my perspective as a sympa-
thetic but critical Project outsider, to productive use by writing a volume summarizing
the DENDRAL research, bringing together in one place for the student, and for archival
purposes as well, the threads of work that had been strung here and there throughout
the literature of computer science and analytic organic chemistry, I agreed to do so.
This background partially explains the pedigree of this volume. The list of authors
might have included every one of the many contributors to the research, but it has
been limited to the major originators and long-term directors of the computer science
directions of the Project, plus myself. As it has developed, I have written almost all the
text; Bruce Buchanan has made major contributions of text and reviewed every draft
of the entire manuscript. Edward Feigenbaum and Joshua Lederberg, of course, have
been the major forces directing the entire project and gave invaluable assistance and
consultation in the preparation of this book.
A large number of people remain who deserve a lot of credit. I would first like to
thank Harold Brown, Ray Carhart, Geoff Dromey, and Dennis Smith, who directly
helped me to understand specific aspects of the Project, and who reviewed my telling
of those stories. Each of them has devoted a generous amount of time to this effort.
Also, I would like to give special acknowledgment and thanks to Maija Kibens for her
help with the entire work, and to Nils Nilsson for his valuable comments.
Additionally, there are many contributors to the Project itself who deserve ac-
responsible
knowledgment in this volume. Those, in addition to the authors, who are
xi
xii PREFACE
for most of the artificial intelligence concepts are Raymond Carhart, Carl Djerassi,
Dennis Smith, Harold Brown, Allan Delfino, Geoff Dromey, Alan Duffield, Neil Gray,
Larry Masinter, Tom Mitchell, James Nourse, N. S. Sridharan, Georgia Sutherland, and
William White.
Other Project contributors have been M. Achenbach, C. Van Antwerp, A. Buchs,
L. Creary, L. Dunham, H. Eggert, R. Engelmore, F. Fisher, R. Gritter, S. Hammerum,
L. Hjelmeland, A. Lavanchy, S. Johnson, J. Konopelski, K. Morrill, T. Rindfleisch, A.
Robertson, G. SchrolI, G. Schwenzer, Y. Sheikh, M. Stefik, T. Varkony, A. Wegmann,
W. Yeager, and A. Yeo.
The financial sponsorship of such an extended effort is extremely important. The
Project has been made possible by the vision of funding-agency executives who have
realized the importance of long-range commitments for such research. In its early years
DENDRAL research was sponsored by the National Aeronautics and Space Adminis-
tration and the Advanced Research Projects Agency of the Department of Defense.
More recently the Project has been sponsored by the National Institutes of Health
(Grant RR-00612). The Project depends on the SUMEX computing facility located at
Stanford University. This facility is sponsored by the National Institutes of Health
(Grant RR-00785) as a national resource for applications of artificial intelligence to
medicine and biology.
The expository portions of the manuscript have been written for some time, but
the completion of the book has been delayed. The main reason for this delay, aside
from the inevitable desire to include mention of each new development in a project
that will never be completed, is in the difficulty we, the authors, have had in sum-
marizing (and agreeing on) what we see to be the Project’s lessons for computer sci-
ence and artificial intelligence. Its appearance at this time does not signal the resolution
of our problem as much as our frustration with it and with the time it has taken us to
formulate our answers. Needless to say, we are not entirely happy with the result.
Hopes and visions, we suppose, always seem much more grand than can be forcefully
argued to others. We have tried not to overstate the case; I hope the reader will see
some of the vision nonetheless. I especially hope that the importance of some of the
specific insights the project members have developed will be appreciated by and will
benefit at least the sympathetic readers,
This book is written primarily for an audience of computer scientists (not just
artificial intelligence researchers), but it will be comprehensible to most nonspecialists
who have a general technical background. The book presumes no knowledge of chem-
istry beyond the level of an introductory college course on general chemistry and no
knowledge of computer science beyond the level of a basic course in computer pro-
gramming. Our aim is to describe and evaluate the Project’s work as an example of arti-
ficial intelligence research, and only secondarily to discuss its importance to chemistry.
Robert Lindsay
Ann Arbor, Michigan
APPLICATIONS OF
ARTIFICIAL INTELLIGENCE FOR
ORGANIC CHEMISTRY
The DENDRAL Project
CHAPTER
ONE
INTRODUCTION
The DENDRAL Boject began with Lederberg’s construction in 1964 of an algo-
rithm for generating canonical names and structural descriptions of molecules. In 1965
the Project’s goals broadened to include interpretation of analytical chemical data us-
ing methods of artificial intelligence.
The DENDRAL Project is a study of scientific reasoning. More specifically, it is an ap-
plication of computer science to the problem of molecular structure ehrcidation in or-
ganic chemistry: the determination of the topological structure of organic compounds
from indirect observations of these compounds with the empirical procedures of mod-
ern chemistry such as mass spectrometry. The computer programs that are the result
of this work are products of artificial intelligence (AI) research, the branch of com-
puter science that undertakes the challenging but controversial task of mechanizing
perception and thought. AI is distinguished from other applications of computers by its
attention to problems for which no straightforward, assured solution methods are
known in advance. In particular, the programs we will discuss employ guessings trategies
and similar rules of thumb called heuristics. This approach to artificial intelligence is
called heuristic programming. Our book describes the structure elucidation problem,
the DENDRAL programs, and the current directions of the Project.
Within computer science the DENDRAL Project is noteworthy in several ways. It
was the first major application of heuristic programming to experimental analysis in an
empirical science, a practical problem of some importance. It was the first large-scale
program to embody the strategy of using detailed, task-specific knowledge about the
problem domain as a source of heuristics, and to seek generality through automating
the acquisition of such knowledge. It has achieved a high level of performance because
it uses a substantial amount of knowledge of chemistry. It is one of the larger, more
sustained AI projects undertaken, giving it a certain prominence even apart from its
successes.I t is being used by chemists, other than its developers, in the pursuit of their
own research goals. It is an interdisciplinary project that has been continuously pro-
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