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Essays on QSAR History
I
began my professional career at the dawn of
this new era, spawned by bursts of creativity and technological advances.
I was a contributor to this paradigm in those formative years and was
also a chronicler of much of the early work in one branch of what is now called
QSAR. I will draw upon these memories and offer them to you in the
belief that you will cast these and other contributions into a meaningful and
accurate historical and archival document. Let
me begin by offering a definition of what should be included in the term QSAR.
In my opinion, this term should embrace attempts to relate biological
activities and properties with attributes of molecules.
These attributes may be classified into three groups: 1) structure
- defined as a model of the form of a molecule, 2) properties - defined
as measured functions of a molecule, and 3) codes - assigned indices or
descriptors that catalogue a molecule or its features outside of the definitions
for structure or properties. In
more detail, some comments on each category are useful. 1.
Structure Structure
is a model of an object (molecule). It
is an abstraction of the whole, created to define, encode or classify one aspect
of the whole molecule. Structure is
not measured, it is modeled using some coherent, consistent scheme.
Examples of schemes to model structure include molecular
orbital-calculated electron charge distributions, energy levels and total
energies, plus topological indices
and conformational predictions.
Properties
are attributes that are measured as a result of the intrusion of some form of
energy into a molecular system. Numerical
values, usually averages over a very large number of molecules arise from this
process. Examples include partition
coefficients, boiling points, pKa values and so on. 3.
Codes Codes
are numerical or descriptive labels that are assigned to a molecule or fragments
to represent that entity in a relationship with some property.
The codes are not defined by elements of structure or properties. They
are arbitrary indices that are useful for a limited span of information. The
KEYS assigned to functional groups are an example. Another example are the
indicator variables used in selected situations in QSAR modeling. A recent
treatment of these attributes is found in: B. Testa and L. Kier " The
Concept of Molecular Structure in Structure-Activity Relationships and Drug
Design" Med. Res. Rev., [11] 35-48
(1991). The
purpose of these preliminary remarks is to insure that all of the early work
leading to models of biological activity is included in the term called QSAR and
historical reviews on this subject. Many
contributions were made before the term was coined.
Since that time there has been some tendency to limit the meaning of QSAR
to property-defined molecular attributes modeling biological activity.
It is a much more inclusive term and I want to elaborate here on the
early work in one branch of the general paradigm. In
the decade of the 1960's, there were formed two distinct approaches to
quantifying molecular attributes with biological activity. The earlier approach, with contributions from
Pullman and Streitwieser in the 1950's, related
molecular activity to molecular
orbital-calculated values. This was
followed by the development of physical property-activity relationships in 1964,
pioneered by Hansch. Each of these
approaches belongs under the rubric of QSAR. At this writing I want to focus on the origins of the
molecular orbital approach to QSAR, describing events of the 1960's.
I have asked my colleague (of 28 years), Lowell Hall to contribute to you
his recollections of the early days of another structure-based approach to QSAR,
namely the use of topology to define structure. In
the structure-based studies in QSAR, one must begin by identifying the
pioneering work of Bernard and Alberte Pullman in the 1950's and beyond.
They utilized the simple Huckel molecular orbital (M.O.)
approximation to study hydrolysis, carcinogenesis, and other biochemical
reactions. Much of their early work
was published in a very influential book, Quantum Biochemistry (1963). Another pioneer at that time was Andrew Streitwieser
who analyzed the relationship between organic chemical reactions and Huckel M.
O. calculated parameters. He also
published a book, Molecular Orbital Theory for Organic Chemists, (1961), that
was to influence a number of scientists to pursue the modeling route to
scientific understanding. I was
strongly influenced by both books. Other
pioneering efforts contributed to the ability to calculate these parameters and
to model molecular activities and properties.
These included the first attempt at an all-valence electron M. O. method
by Del Re in 1958, the first all-valence electron method capable of predicting
conformational preferences by Hoffmann in 1963, and the first all-valence
electron method giving reasonable charges by Pople in 1965.
Many others contributed to the methodology by creating increasingly more
sophisticated M. O. methods. The
early work using these methods was largely focused on biochemical reactions and
interactions. Several symposia were
held during this decade. These
included the Menton, France series sponsored by the Pullmans, the Jerusalem
symposia begun in 1967, Gordon
Conferences devoted to quantum mechanical calculations, and the Sanibel Island
Conferences. The main focus
of these meetings was M.O. development and applications primarily in chemical
reactivity. At each symposium,
there was always an invited biologist or two who would attempt to relate the
theoretical methods to explain a biological phenomena.
I found myself in this role on several occasions.
Attempts to relate structure to drug activity was a presentation usually
on the last day of the meeting and it would appear as the last chapter in the
symposium volume. At
one of the Sanibel meetings in the late 1960's an organization was formed called
the International Society of Quantum Biology.
I was on the board of this organization for two years.
I wonder if this was not the antecedent or direct stimulus for the
formation of the QSAR Society? There
were a number of scientists, impressed by the work of the Pullmans and
Streitwieser who ventured into the drug molecule structure-activity realm using
these methods. Some interesting
work was published by a handful of investigators but it was not warmly received
at that time by the medicinal chemists, the quantum people or the
property-activity modelers. One
significant contribution occurred in 1967 when the first M. O. calculation of
the preferred conformation of a drug molecule was reported.
The molecule was acetylcholine, Kier, (1967).
The prediction was later confirmed experimentally.
Further studies in this series on other transmitters and drugs led the
way to the predictions of pharmacophores using the technique labeled
"receptor mapping". The
prediction of preferred conformation is now an automatic procedure that all
modelers accomplish by clicking on an icon to "minimize".
The first symposium devoted primarily to applications of M.O. studies on drug molecules was organized by Kier in 1969 in Seattle, Wash. This was sponsored by Battelle Memorial Institute. All of the investigators using M.O. in QSAR studies at that time were in attendance. The speakers included: Art Cammarata, Bill Purcell, Soloman Snyder, Jack Green, Brock Neely, Arnie Wohl, The
latest work in structure-based QSAR was presented at the symposium.
The symposium book from this meeting, the first book dealing with drug
QSAR, was published the following year: Molecular
Orbital Studies in Chemical Pharmacology, L. B. Kier, ed.
(1970). The QSAR studies in
the 60's using molecular orbital theory were summarized in a primer on the
subject, published in 1971: Molecular Orbital Theory in Drug Research, L. B.
Kier (1971). These
were the events in the first decade of structure-based QSAR studies that I
recall. I can look for memorabilia
and more details as you wish. I
hope that I have not omitted anyone but that will surface as you work on this
project. Lowell and I will continue
the effort to assist you and look forward to your comments.
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