MYCIN PROJECT Section 6.1.4

II) Interactions with Sumex-Aim resource

Collaborations and medical use of programs
Dr. Jon Heiser

We have been working with Dr. Jon Heiser of the Department of Psychiatry of
the University of California at Irvine, in an effort to create a consultant for
the use of psychoactive drugs. We began by creating a version of Mycin that had
all of the infectious disease knowledge removed from it, and showed Dr. Heiser
how to build up the required base of knowledge about the new field.

He has, with his students, developed a small, but functional system that
demonstrates encouraging performance on the task. Work has now begun in earnest
to extend the competence of this pilot system, to produce a consultant with a
useful level of performance,

It is interesting to note that the explanation capabilities required no

modification whatever, and worked in the new system exactly as designed for the
original system, despite the change in domains.

Privileged Communication 101 J. Lederberg
Section 6.1.4 MYCIN PROJECT

INTERNIST Project

The Sumex computer has made possible a valuable interaction between
researchers on the MYCIN project at Stanford University and those working on the
INTERNIST project at the University of Pittsburgh. These researchers are
Studying the possible representations and uses for disease models in a medical
diagnosis system. Both research groups have been able to run each others
programs and to study the medical knowledge bases which are stored on the Sumex
computer. Communication between project members has also been greatly
facilitated through use of the Sumex system.

Stanford Infectious Disease Faculty

Dr. Victor Yu of our group has been actively soliciting the involvement of
the Stanford ID faculty in the development and evaluation of Mycin. He recently
presented the system to the faculty and fellows of the Department, and has been
seeking ways to involve the system in the Department’s educational activities.
For instance, medical students under his supervision have used the system during
their ID rotation, comparing its results and reasoning process with their own on
problems encountered in patients on the wards.

The Pulmonary Function Facility

Members of the Mycin project have also been collaborating with Dr. John
Osborn and his co-workers of the Presbyterian Hospital/Pacific Medical Center in
San Francisco on the development of a program to interpret the results of
standard pulmonary function tests. The program is designed to perform a range of
tasks, including: identifying the need to repeat tests because of poor patient
effort; identifying the need for additional information in order to make a more
definitive diagnosis; reporting and explaining the reasons for primary and
secondary diagnoses and severity of any disease State; identifying the relation
between diagnosis and any referral diagnosis; and interpreting any change from
previous tests, or limitations on the interpretation because of the test
methodology and the patient effort.

Sharing with other projects

Groups at Rutgers University, the University of Pittsburgh, Rochester
University, and the University of Virginia Medical School have all been involved
in varying degrees with running Mycin and evaluating its performance. They have
suggested to us improvements in its design, and stock of medical knowledge, and
made useful contributions to its development.

In addition, we have made use of the programs developed at both Rutgers and

Pittsburgh. The former has been instructive to us in its handling of dynamically
changing situations, while the latter has helped us to develop our own ideas
about the modelling and use of prototypical descriptions of disease states.

The Molgen group at Stanford has also profited from much of our experience
in acquiring knowledge and building large knowledge bases. Several of their

J. Lederberg 102 Privileged Communication
MYCIN PROJECT Section 6.1.4

techniques for accumulating knowledge about genetics are based on extensions to
ideas first suggested in some of our work.

In all of these cases, the use of Sumex as a national resource has clearly
been a critical factor in making possible this sort of interaction.

Privileged Communication 103 J. Lederberg
“YCIN PROJECT Section 6.1.4

References

(1] Reiman H H, D’ambola J, The use and cost of antimicrobials in hospitals, Arch
Environ Health, 13:631-636 (1966).

[2] Kunin C M, et.al., Use of antibiotics: a brief exposition of the problem and
some tentative solutions, Anns Int Med, 79:555~-560 (1973).

[3] Sheckler WE, Bennett J V, Antibiotic usgae in seven community hospitals, J
Amer Med Assoc, 213:264-267 (1970).

[4] Roberts A W, Visconti J A, The rational and irrational use of systemic
antimicrobial drugs, Amer J Yosp Pharm, 29:3828-834 (1972).

mo
UI
ce

Sinnons H E, Stolley P D, This is medical progress? Trends and consequences
of antibiotic use in the United States, J Amer Med Assoc, 227:1023-1026
(1974).

[6] Kagan BM, Fanin SL, Bardie F, Spotlight on antimicrobial agents, JAMA,
226 : 306-310 (1973).

Privileged Communication 107 J. Lederberg
Section 6.1.5 PROTEIN STRUCTURE PROJECT

6.1.5 PROTEIN STRUCTURE PROJECT

Protein Structure Modeling Project

Prof. J. Kraut and Dr. S. Freer (Chemistry, U. C. San Diego) and
Prof. &. Feigenbaum and Dr. R. Engelmore (Computer Science, Stanford)

I. Summary of research program

 

A. Technical goals

The goals of the protein structure modeling project are to 1) identify
critical tasks in protein structure elucidation which may benefit by the
application of AI problem-solving techniques, and 2) design and implement
programs to perform those tasks. We have identified two principal areas which
have both practical and theoretical interest to both protein erystallographers
and computer scientists working in AI. The first is the problem of interpreting
a three-dimensional electron density map. The second is the problem of
determining a plausible structure in the absence of phase information normally
inferred from experimental isomorphous replacement data. Current emphasis is on
the implementation of a program for interpreting electron density (e.d.) maps.

B. Medical relevance and collaboration

The biomedical relevance of protein crystallography has been well stated in
a recent textbook on the subject (Blundell & Johnson, Protein Crystallography,
Academic Press, 1976):

"Protein Crystallography is the application of the
techniques of X-ray diffraction ... to crystals of one
of the most important classes of biological molecules,
the proteins. ... It is known that the diverse
biological functions of these complex molecules are
determined by and are dependent upon their
three-dimensional structure and upon the ability of
these structures to respond to other molecules by
changes in shape. At the present time X-ray analysis of
protein crystals forms the only method by which detailed
structural information (in terms of the spatial
coordinates of the atoms) may be obtained. The results
of these analyses have provided firm structural evidence
which, together with biochemical and chemical studies,
immediately suggests proposals concerning the molecular
basis of biological activity."

The project is a collaboration of computer scientists at Stanford
University and crystallographers at the University of California at San Diego
(under the direction of Prof. Joseph Kraut) and at Oak Ridge National
Laboratories (Dr. Carroll Johnson).

J. Lederberg 108 Privileged Communication
PROTEIN STRUCTURE PROJECT Section 6.1.5

C. Progress summary

During the past year we have been designing and implementing a system of
programs for interpreting three-dimensional e.d. maps. Progress has been made by
attacking the problem from two directions: working upward from the primary data
(i.e. the array of e.d. values) to higher level symbolic abstractions, and
working downward from the given amino acid sequence and other experimental
information to generate candidate structures which can then be confirmed by the
abstracted data.

In the "bottom-up" area of research we have developed and implemented
programs for analyzing topological features of the skeletonized e.d. may in terms
of protein structural elements (e.g., side chains, enain ends, bridges, etc.),
for finding local maxima, and, recently for generating a critical point network,
i.e. a three-dimensional spanning tree which connects all critical points
(peaks, saddle points) found in the map.

In the "top-down" area we have designed and implemented, in INTERLISP, a
Structure inference program which generates structural hypotheses at several
levels of detail. At present the program can infer, from the amino acid sequence
and other chemical information, and the symbolic abstractions of the e.d. map,
the location of heavy atoms, cofactors and chain ends. Those features provide
toeholds, i.e. islands of certainty, from which additional structure is inferred
vy extension. Work is currently in progress on identification of the main chain,
disambiguation of multiply connected regions and classification of side chain
regions.

The system under development is knowledge-based. Both the corpus of
knowledge of the task domain and the problem-solving strategy knowledge are
incorporated as production-like rules.

D. List of Publications

1) Robert S. Engelmore and H. Penny Nii, "A Knowledge-Based System for the
Interpretation of Protein X-Ray Crystallographic Data," Heuristic Programming
Project Memo HPP-77-2, January, 1977. (Alternate identification: STAN-CS-77-
589)

2) E.A. Feigenbaum, R.S. Engelmore, C.K. Johnson, "A Correlation Between

Crystallographic Computing and Artificial Intelligence," in Acta
Crystallographica, A33:13, (1977). (Alternate identification: HPP-77-25)

Privileged Communication 109 J. Lederberg
Section 6.1.5 PROTEIN STRUCTURE PROJECT

II. Interaction with the SUMEX-~AIM resource

A. Collaborations

The protein structure modeling project has been a collaborative effort
since its inception, involving co-workers at Stanford and UCSD (and, more
recently, at Oak Ridge). The SUMEX facility has provided a focus for the
communication of knowledge, programs and data. Without the special facilities
provided by SUMEX the research would be seriously impeded. Computer networking
has been especially effective in facilitating the transfer of information. For
example, the more traditional computational analyses of the UCSD crystallographic
data are made at the CDC 7600 facility at Berkeley. As the processed data,
specifically the e.d maps and their Fourier transforms, become available, they
are transferred to SUMEX via the FTP facility of the ARPA net, with a minimum of
fuss. (Unfortunately, other methods of data transfer are often necessary as well
-- see below.) Programs developed at SUMEX, or transferred to SUMEX from other
laboratories, are shared directly among the collaborators. Indeed, with some of
the programs which have originated at UCSD and elsewhere, our off-campus
collaborators frequently find it easier to use the SUMEX versions because of the
interactive computing environment and ease of access. Advice, progress reports,
new ideas, general information, ete. are communicated via the message and/or
bulletin board facilities.

B. Interaction with other SUMEX-AIM projects

Our interactions with other SUMEX-AIM projects have been mostly in the form
of personal contacts. We have strong ties to the DENDRAL, Meta-DENDRAL and
MOLGEN projects and keep abreast of research in those areas on a regular basis
through informal discussions. The SUMEX-AIM workshop in June, 1976 provided an
excellent opportunity to survey all the projects in the community. Common
research tnemes, e.g. knowledge-based systems, as well as alternate problem-
solving methodologies were particularly valuable to share. (That workshop was
very likely the most significant conference for applied AI to be held in 1976.)

J. Lederberg 110 Privileged Communication
Section 6.2 NATIONAL AIM PROJECTS

6.2 NATIONAL AIM PROJECTS

The following group of projects is formally approved for access to the AIM
aliquot of the SUMEX-AIM resource. Their access is based on review by the AIM
Advisory Group and approval by the AIM Executive Connittee.

J. Lederdarg 112 Privileged Connunieation
ACQILSITION OF COGNITIVE PROCEDURES (ACT) Section 6.2.1
6.2.1 ACQUISITION OF COGNITIVE PROCEDURES (ACT)

Acquisition of Cognitive Procedures (ACT)

Dr. John Anderson
Yale University

I. Summary of Research Progran

A. Technical goals:

To develop a production system that will serve as an interpreter of the
active portion of an associative network. To model a range of cognitive tasks
including memory tasks, inferential reasoning, language processing, and problem
solving. To develop an induction system capable of acquiring cognitive
procedures with a special emphasis on language acquisition.

B. Medical relevance and collaboration:

1. The ACT model is a general model of cognition. It provides a useful
model of the development of and performance of the sorts of decision
making that occur in medicine.

2. The ACT model also represents basic work in AI. It is in part an attempt
to develop a self-organizing intelligent system. As such it is relevant
to the goal of development of intelligent artificial aids in medicine.

We have been evolving a collaborative relationsnip with Dr. James Greeno
and Allan Lesgold at the University of Pittsburgh. They are applying ACT to
modeling the acquisition of reading and problem solving skills. We plan to make
ACT a guest system within SUMEX. ACT is currently at the state where it can be
shipped to other INTERLISP facilities. We have received a number of inquiries
about tne ACT system. ACT is a system in a continual state of development ‘ut we
periodically freeze versions of ACT which we maintain and make available to the
national AI community.

Cc. Progress and accomplishments:

ACT provides a uniform set of theoretical mechanisms to model such aspects
of human cognition as memory, inferential processes, language processing, and
problem solving. ACT’s knowledge base consists of two components, a
propositional component and a procedural component. Tne propositional component
Ls provided by an associative network encoding a set of facts known about tne
world. This provides the system’s semantic memory. The procedural component

Privileged Communication 113 J. Lederberg
Section 6.2.1 ACQUISITION OF COGNITIVE PROCEDURES (ACT)

consists of a set of productions which operate on the associative network. ACT’s
production system is considerably different than many of the other currently
available systems (¢.g., Newell’s PSG). These differences have been introduced
in order to create a system that will operate on an associative network and in
order to accurately model certain aspects of human cognition.

A small portion of the semantic network is active at any point in time.
Productions can only inspect that portion of the network which is active at the
particular time. This restriction to the active portion of the network provides
a means to focus the ACT systena in a large data base of facts. Activation ean
Spread down network paths from active nodes to activate new nodes and linxs. To
prevent activation from growing continuously there is a dampening process whiten
periodically deactivates all but a select few nodes. The condition of a
production specifies that certain features be true of the active portion of the
network. The action of a production specifies that certain changes be made to
the network. #ach production can be conceived of as an independent “demon.” Its
puppose is to see if the network confizuration specified in its eonlition is
satisfied in the active portion. If it is, the production will axeeute and ease
chaages to memory. In so doing it can allow or disallow other productions which
are looking for their conditions to be satisfied. Both the spread of activation
and the selection of productions are parallel processes whose rates are
controlled by "strengths" of network links and individual productions. Ana
important aspect of this parallelisn is that it is possible for multiolsa
yeoductions fo o= applied in a cycle through the sat of peodagtioas. Maca of faa
zarly work on the ACT systen was foeusel on developing ooapabational deviees to
reflect tne operation of parallel, strength-controlled processes and working out
the logic for creating functioning systems in such a computational medium.

We have successfully implemented a number of small-scale systems that model
various psychological tasks in the domain of memory, languaze processing, and
inferential reasoning. A larger scale effort is underway to model the language
provessing dechanisns of a young child. This includes implementation of a
production system to analyze linguistic input, make inferences, ask and answer
questions, etc. Also a great deal of effort is being given to developing
learning mechanisms that will acquire and organize the productions for this
language processing. This learning program attempts to acquire procedlures fron
examples of the computations jesirei of the procedures. For instance, the
progran learns to comprehend and generate sentences by being zivea seatences and
ploature representations of the meaning of the sentences (actually hand encodings
of the pictures). Although this effort is focused on induction of linguistic
procedures, the hope is to develop a general model of induction of cognitive
procedures and not to place any language-specificity into the induction
procedures.

At the time of this report, we have completed the F version of ACT which is
tne system with learning capabilities. We are currently testing and tuning the
system on a nunber of linguistic examples. Other projects which are progressing
in earlier versions of ACT include use of spreading activation to model semantic

disambiguation, modeling of the reading process, and modeling of solutions to
word arithmetic problems.

J. Lederberg 114 Privileged Communication
ACQUISITION OF COGNITIVE PROCEDURES (ACT) Section 6.2.1

D. Current List of project publications:

[1] Anderson, J.R. Computer simulation of a Languaze acquisition 3
second report. In D. LaBerge and S.J. Samuels (fds.). Paroent

perceptioy Ade

Comprehension. dillsdale, N.J.: L. Erlbaum Assoc., 1976.

[2] Anderson, J.R. Language, Memory, and Thought. Hillsdale, N.J.: L. Erlbaum,
Assoc., 1976.

 

[3] Anderson, J.R. Induction of augmented transition networks. Soznitive
Science, 1977, in press.

[4] Anderson, J.R. & Kline, P. Design of a production Systsa. Paper to ba
presented at the Workshop on Pattera-Directel Inferenos Systeas, Jawail, “May
23-27, 1977.

[5] Anderson, J.R., Kline, P. & Lewis, C. Language processing by production
systems. To appear in P. Carpenter and M. Just (Eds.). Cognitive Processes
in Comprehension. L. Erlbaum Assoc., 1977.

{6] Kline, P.J. & Anderson, J.P. The ACTE Jser’s Manual, 1976.

Ii. Interaction With the SUMEX-AIM Resource

 

The SUMEX-AIM resource is superbly suited for the needs of our project. We
nave made the most extensive use of the INTERLISP facilities and the facilities
for communication on the ARPANET. We have found the SUMEX personnel extremely
helpful both in terms of responding to our immediate emergencies and in providing
advice helpful to the long-range progress of the project. Despite the fact that
we are on the other side of the continent, we have felt almost no degradation in
our ability to do research. We find we can easily list 01 the terminal a small
portion of programs under modification. The willingness of SUMEX mail listing
has also meant we can keep relatively up-to-date records of all programs under
development.

A unique east coast advantage of working with SUMEX is the low loading of
the system during the mornings. We have been able to get a great deal of work
Jone during tnese hours and try to save our computer-intensive work for these
nours,

We have found our one AIM work shop so far (1976) a very useful opportunity
to meet with colleagues and exchange ideas.

A particularly striking example of the utility of the SUMEX resource was
illustrated in the move from Michigan. In the summer of 1976 Anderson moved to
Yale and Greeno to Pittsburgh. There was no loss at all associated with having
to transfer programs from one system to another. At Yale we were programming the
day after we arrived. The SUMEX link has also permitted continued collaboration
with Greeno.

Privileged Communication 115 J. Lederberg
Section 6.2.2 CHEMICAL SYNTHESIS PROJECT (SECS)

6.2.2 CHEMICAL SYNTHESIS PROJECT (SECS)

SECS —- Simulation and Evaluation of Dienteal Synthesis

wW. Todd Wipxe
Department of Chenistry
Jaiversity of California at Santa Cruz

I. Summary of Research Program

A. Technical Goals.

The long range goal of this project is to develop the logical principles of
molecular construction and to use these in developing practical computer programs
to assist investigators in designing stereospecific syntheses of complex bio-
organic molecules. Our specific goals this past year focused on improvement of
the library of chemical transforus, completion of the perception of molecular
synmetry and integrating the use of symmetry infornation throughout SEC
including the strategy module. We also wanted to improve the execution speed of
SECS, and the speed of graphical interaction over remote communication lines. We
planned to simplify tne program from the user’s viewpoint by including automatic
file failsafing, improvement of HELP commands, and non-fatal handling of all
errors, as well as production of user’s manuals for operation of the program and
the writing of chemical transforms. Additionally we intended to initiate
applications of SECS to the areas of biosynthesis and metabolism of compounds, as
well as phosphorus chemistry. Finally we hoped to improve the strategic
constraints and controls that guide SECS in growing a synthesis tree.

B. Medical Relevance and Collaboration.

Tne development of new drugs and the study of how drug stracture is related
to biological activity depends upon the chemist’s ability to synthesize new
molecules as well as his ability to modify existing structures, e.g.,
incorporating isotopic labels into biomolecular substrates. The Simulation and
Evaluation of Chemical Synthesis (SECS) project aims at assisting the chemist in
designing stereospecific syntheses of biologically important molecules. The
advantages of this computer approach over a manual approaches are manyfold: 1)
greater speed in designing a synthesis; 2) freedom froa bias of past experiences
and past solutions; 3) thorough consideration of all possible syntheses using a
more extensive library of chemical reactions than any individual person can
remember; 4) greater capability of the computer to deal with the many structures
which result; and 6) capability of computer to see molecules in graph theoretical
sense, free from bias of 2-D projection.

SECS was designed to be able to apply any kind of chemical transfornation,
4nd because of this generality we see SECS finding application in biogenesis and
metabolism (see section II A below). The objective of using SECS in biogenesis
is to predict possible biogenetic pathways for a given natural product and also

J. Lederberg 118 Privileged Communication
CHaMICAL SYNTHESIS PROJECT (SECS) Section §.2.2

to predict related compounds which might also co-occur in nature. This can be a
great aid in searching for new natural products and in structure elucidation.

The objective of using SECS in metabolism is to predict the plausible
metabolites of a given xenobiotic in order that they may be analyzed for possible
carcinogenicity. Metabolism research may also find this useful in the
identification of metabolites in that it suggests what to look for, and in the
identification of possible metabolic pathways connecting a metabolite to a
xenobiotic.

C. Progress and Accomplishments.

RESEARCH ENVIRONMENT: At the University of California, Santa Cruz, we have
a GT-40 graphics terminal connected to the SUMEX-AIM resource by a 1200 baud
leased line and a TI 725 thermal printing teletype connected via TYMNET at 300
baud. UCSC has only a small IBM 370/145 and a PNP-11/45 (limit of 12 K words per
user) available, both of which are unsuitable for this raseareh. Froa July until
December our research group had to occupy temporary space during renovation, dat
i3 now finally in permanent space in Taimann Laboratories where we have close
collaboration with other organic chemists.

CHEMICAL TRANSFORMS: The library of chemical transforms has been
reorganized and reevaluated during the past year by Mr. Dolata, a student of
Professor D.A. Evans of Cal Tech. New reactions were added and the seope and
limitations of others were updated and leading references provided.

Additionally, Merck, Sharp, and Dohme Research Laboratories provided revisions of
“any transforms which a group of 25 synthetic chemists had carefully researched.

SYMMETRY: An efficient algorithm for recognizing molecular symmetry was
developed last year. This year that algorithm has been tested against all
possible molecular point groups and a few problems which developed were
corrected. The algorithm has been docuwnented and initial studies begun on
actually determining the point group of a molecule. The symmetry group is now
utilized in conjunction with the symmetry of a chemical transfora so the
transform is applied in all possible unique ways, to generate a non-redundant set
of precursors. This symmetry of course takes into account stereochemistry of
Saturated centers and double bonds. We have surveyed literature syntheses for
examples of existing heuristics based on symmetry which can be used for
automatically generating high level strategies. This information has never been
pulled together before and should make an interesting contribution also to
organic synthesis.

STRATESIC CONTROL: Last year we began developing an implementation of
strategic control for SECS, and a simple language for expressing strategies
independent of chemical transforms. Since these strategies contain expressions
wnich refer to the molecular structure, it was also necessary to iacorporate
syumetry here too. For example, if a particular bond is designated as strates ia
%2 Dreak, but a transform breaks another bond, the Strategy is still satisfied if
ti2 two bonds are equivalent by symmetry. This problem becomes more complex when
pairs of bonds are specified and when there are logical connectives (AND, OR,
XOR, and NOT) involved. This has however been solved. Other changes since last
year include a completely new user interface to strategy to allow error

Privileged Communication 119 J. Lederberg
Section 3.2.2 CHEMICAL SYNTHESIS PROJECT (Sees)

2orrection and very easy modification of goals, Finally quantitakive excnsrinaats
‘ave been performed to measure the effect of leveloping a sy ibiesis teee with
various types of strategic constraints. The net result of tais work is tnat bhe
user can more easily constrain SSCS now to work only in areas which the user
decides are worthwhile, consequently fewer precursors are generated which the
user would delete.

USER INTERFACES: Users of SECS had difficulty understanding how to copy
files into work areas in order to save or restore syntnesls teaas. Wow SECS does
all file manipulation, eliminating the problem. Further 3EC3 aow automatically
Pfailsafes the syathesis tree at key points so that in the avent of machine or
communicatioa failure the user can automatically restart his analysis from the
last key point. Considerable modifications were made to the graphical interface
for increasing readability and speed of interaction. Over long slow
communication lines (which happens to be the way most SECS users are accessing
the program) interactive graphics must be done with care, minimizing the amount
and frequency of picture transmission, in order to achieve aven tolerable man-—
aasnine comaunieation, Lastly, we have implemented approoriate Liput progsiures
to eliminate the possibility of a fatal crash from user input errors. According
to user reports this was a major problem.

PHOSPHORUS CHEMISTRY: Graphical input and output procedures were developed
for entering the stereochemical configuration of a trigonal bipyrimid (TBP)
phospnorus atom and for producing a correct structural diagraa fron the machine’s
internal representation. The 3EMA algoritnna for generating a stereochemizally
uiique name was extended to deal with the 29 908SLbLe configaraelors Te aay, 73?
»21ber, including the ability to recognize enantiouars, Tia AUCHS4 Laazgaara for
eap-2senting chemical transforms was extended to facilitate manipulation of
TBP’s, including changes from trigonal and tetrahedral configurations to square
base pyramid and TBP. Queries may deal with apicophilicity, and axial or
equatorial orientation. The fine details of phosphorus chenistry such as the
fact that groups entering or leaving the phosphorus coordination sphere aornally
do 30 from the apical position. Pseudo rotation, apiaophilteity, avl sbeain
24303y are 2913iderad in evaluating thea stable TBP 202afiguratiogs aa ia eheaktlag
Por Lleatital sobeuatures. A library of phosphorus cheaistey t3 ao4 Sahag
peespared in collaboration with a group at the University of Strasbourg, Prange,

CIMPITER-AIDED ELUCIDATION OF BIOGENETIC PATHWAYS: Althouzn a great amount
of effort has been spent on various areas of biogenesis, there have been few
attempts to develop general techniques for the elucidation of biogenetic schemes.
As a result, the formulation of biogenetic schemes has often been criticized for
its lack of rigor and explicit criteria. Our approacn is to develop zeneral
Ceanniques which lead to the postulation of plaustble biogsanetie pathways, ustaz
tae SECS as an aide in obtaining and analyzing solutions to this ao1aplex prodlea,
It 13 dur hope this application of computer orobdlem solving testiaijaas sili vat
Jyily uncover new ways of recognizing and evaluating biozenetic pathways but also
provide added support to deductions made from biogenetic schemes, such as the
generality of a scheme which may be tested in only a few species.

With the proper input information and goals well defined there may be
explicit rules to guide the chemist to plausible biogenetic pathways for a
particular natural oroduct. Unfortunately, the vast majority of solutions to
tals problem are determinaad dy a conbination of the experiaaned aabural arotuets

J. Gelerburs 129 Privileged Communieation
CHEMICAL SYNTHESIS PROJECT (SECS) Section 6.2.2

chemist ’s ability to consider the most important rules involved and his unique
set of experience-based prejudices. There may be some means to represent and
utilize all of the known relevant rules, data and possibly even experience-based
prejudices to arrive at the best plausible pathways. The most precise method for
representing, developing and testing such a theory is in the form of a computer
program. To implement such a computer program, known rules and constraints must
be clearly defined, then those that are applicable can be applied at each step of
the analysis toward the desired goal. This will keep the solution pathways
logically pure and insure that all alternatives which satisfy the rules and
constraints are considered. This guarantee of completeness simply can not be
made using hand analysis.

A new reaction library containing biogenetic transformations have been
written. After inputting a natural product the program will apply the biogenetic
transforms which fit the natural product. This generates a set of plausible
biogenetic precursors to the target natural product. By continuing this process
with the precursors generated, the plausible biogenetic pathways for the natural
product. can be discovered.

The structures of marine natural products were entered into the program and
the plausible biogenetic pathways for these compounds were generated and
analysed. Biogenetic pathways which had been proposed in the literature were
among the pathways discovered, as were other plausible pathways which would now
have to be considered. The success we attained in this research effort verified
tne applicability of the SECS program as an aid in the analysis of metabolic
pathways.

COMPUTER-AIDED PREDICTION OF METABOLITES FOR CARCINOGENICITY STUDIES: We
have initiated a research project in collaboration with the Chemical
Carcinogenesis group at the National Cancer Institute. The objective of this
research is to establish a computer program by which a biochemist or metabolism
expert can explore the metabolism of a chemical compound. The investigator
enters the substrate molecule by interacting with an input and structure editing
module.

Then the program will apply the biological transforms which "fit" the
structure, taking into consideration all the context information (2-D, 3-D, and
electronic) available about the transform and all perceived information about the
structure. This will generate a set of metabolites which are one step away from
the substrate structure. The metabolites will be ranked according to expected
probability or yield. The exact parameters which should be monitored will be
determined during the course of this research. An evaluation module may then
sereen these metabolites according to criteria specified by the investigator.
Duplicate metabolites arising from different pathways will be labelled to
indicate that fact. Finally the investigator will be shown the set of
metabolites together with data about the transform which produced each one and
the values of the parameters being monitored.

The investigator may select one metabolite for further metabolism or may
request that all be processed for a specified number of steps. In this way a
"tree" of metabolites is produced and displayed. The entire state of the user’s
tree may be saved to permit continuation of the analysis at another time.
Exploration of the metabolism tree will be predominately guided interactively by

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the expert investigator. We feel that at this stage of development of the field
of metabolism and carcinogenicity that interactive guidance by the expert is
necessary. There are many areas where the theory is very thin and a given
biological transformation may have been observed for only a few substrates. When
this transform is applied to a new substrate, some unrealistic metabolites may be
generated owing to the deficiency of contextual information and constraints. An
expert is necessary to prune the tree and prevent the automatic processing of
those unreasonable intermediates. It is much more efficient for the expert to do
this pruning as the tree is being grown, rather than later after an enormous tree
has been completed.

At some point either during tree generation or at the end, the metabolites
will be passed to another program which will identify those metabolites which are

identical or "similar" to known carcinogens. Those will be so marked in the
tree.

Presently, tne major task is the aquisition of the metabolism knowledge
base, i.e. the writing of the transformation library to be utilized. Metabolism
experts at the National Institute of Health are gleaning this information from
both their own research and the metabolism literature. This information will be
encoded and the first testing of this new application for the SECS program will
begin in June 1977.

D. Current List of Project Publications

W.T. Wipke and P. Gund, "Simulation and Evaluation of Chemical Synthesis.
Congestion: A Conformation Dependent Function of Steric Environment at a
Reaction Center. Application with Torsional Terms to Stereoselectivity of
Nucleophilic Additions to Ketones," J. Am. Chem. Soc., 98, 8107(1975).

W.T. Wipke, G. Smith and H. Braun, "SECS-Simulation and Evaluation of Chemical
Syntheses: Strategy and Planning," ACS Symposium Proceedings, 1977.

W.T. wWipke, Computer Planning of Research in Organic Chemistry, Proceedings of

the Third International Symposium on Computers in Chemical Education,
Research, and Technology, Caracas, Venezuela, 19-76.

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S.A. Godleski, P.v.R Schleyer, E. Osawa, and W.T. Wipke, "The Systematic
Prediction of the Most Stable Neutral Hydrocarbon Isomer," J. Am. Chem.
Soc., 99, 0000(1977).

F. Choplin, R. Marc, G. Kaufmann, and W.T. Wipke, "Computer Design of Synthesis
in Phosphorus Chemistry. Automatic Treatment of Stereochemistry," J. Am.
Chem. Soc., 99, 0000(1977).

Manuals:

SECS Users Manual, June 1976.
SECS Users Guide, Aug 24, 1976.
ALCHEM Tutorial, Sep 21, 1976.

Ii. Interactions with SUMEX-AIM Resource

A. Examples of Collaborations and Medical use of Programs via SUMEX.

SECS is available in the GUEST area of SUMEX and has been accessed
experimentally by many others as well. Professor R. V. Stevens (UCLA) explored
some syntheses of lycapodine while visiting Santa Cruz and as a result nas
requested UCLA to obtain a graphics terminal so he and others at UCLA can access
SECS via SUMEX. Professor W. G. Dauben’s group (Berkeley) has utilized the SECS
model builder on SUMEX is now extending the capabilities of that module of SECS.
Mr. Mel Spann of the National Library of Medicine toxicology program is
collaborating with us in developing a metabolism library for the metabolism of
catechol amines. Also collaborating with us on metabolism are Drs. Ted Gram from
Guarino’s lab, Harry Gelboin, Dhiren Thakken and Harukiko Hagi from Jerina’s lab,
Lance Pohl from Gillette’s lab, Sidney Nelson from Mitchell’s lab, Lionel Poirier
from Weisburger’s lab, and Ken Chu and Sidney Siegel all of whom are from the
National Cancer Institute. Dr. Steve Heller of the EPA and Dr. G.A. Milne of
the National Heart and Lung Institute have expressed interest in putting SECS on
the Cyphernetics network as a part of the NIH chemical information system.
Restrictions on the allowed core image on that system have so far held up the
negotiations.

For the past two years SECS has been available over TELENET from First Data
Corporation and has been accessed by industry: Squibb; Merek, Sharp and Dohme;
Pfize; Searle; Lederle Labs; FMC; and recently 3M Corporation and Stauffer. Dr.
Beryl Dominy of Fizer recently presented a paper before the Pharmaceutical
Manufacturer’s Association entitled "SECS and the Information Scientist" in which
he describes his experiences. with SECS, including an example where a synthetic
chemist was having difficulty with a particular synthesis, he then went to SECS

for possible solutions. SECS Suggested another route as being better and indeed
that is what he found when he tried it later in the lab.

The availability of SECS on SUMEX-AIM has also served health-related
research at the University of California, Santa Cruz. Model building using the
SECS model builder is being performed for Professor Edward Dratz (UCSC) to
generate conformations of fatty acids isolated from visual membranes ("Structure

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Section 6.2.2 CHEMICAL SYNTHESIS PROJECT (SECS)

and Function of Visual photoreceptors," E1I00175), and for Professor Howard Wang
(UCSC) to study how conformations of steroids may affect the local anesthetic -
menbrane interaction ("Role of Membrane Proteins in Local Anesthetic Action,"
GM222H2).

We have assisted Professor J. E. MeMurry in his synthetic work towards
Aphidicholine and Digitoxigenin by using the model builder for predicting
possible reaction pathways. 4n example is given below, where the conformation of
the epoxy-ylide was calculated along with the strain energies of the two possible
closure products.

/N

CO om ee OD
Qs er owe OD
oO

Utilizing the SECS model builder, we have shown that attack on the epoxide
to form the fused system should be much more favorable then attack to form the
bicyclo compound. Similar studies have been undertaken to predict the
stereochemistry resulting from the acid catalyzed cyclization of MeMurry’s
Digitoxigenin precursor (HL-18118 "Total Synthesis of Cardiac Aglycones."):
application of SECS using a special library of cationic sigmatropic rearrangement
transforms generated the possible products which facilitated identification of
some of the side products in the early cyclization experiments. We have also
collaborated in the biogenesis work with Professor Phil Crews (UCSC) in marine
natural product biogenesis. Dr. Wipke has also used several SUMEX programs such
as CONGEN in his course on Computers and Information Processing in Chemistry.

B. Examples of Sharing, Contacts and Cross-fertilization with other
SUMEX-AIM projects.

In collaboration with Dr. Ray Carhart and Dr. Dennis Smith of the
DENDRAL/CONGEN Project, a Computers in Chemistry Workshop was held at U.C. Santa
Cruz on the weekend prior to the Fall 1976 American Chemical Society National
Meeting held in San Francisco. The workshop attracted participants representing
all parts of the chemical community, academia, industry and government. Morning
lecture/discussion sessions introduced the SECS and CONGEN programs running on

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SUMEX and the afternoon and evening sessions allowed "hands-on" experience for
the participants. The response of the workshop participants was a very positive
one with many participants showing so much interest that future collaboration

and/or use of the powerful non-numerical computing tools available on SUMEX was
discussed.

The SECS project has held joint research group meetings at Stanford with
the DENDRAL and AI groups to discuss common problems and research goals. This
has been very rewarding since the groups are complementary in orientation. These
joint meetings also let the members meet in person after having met on-line on
the network. Last year’s AIM Conference at Rutgers was also a valuable
experience, which allowed us to meet people interested in similar problems in
different disciplines. It was particularly useful to have the opportunity to
talk with experts designing new languages for knowledge representation and to
hear them compare their systems.

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