Semiempirical references.
Fellow Netters,
Below is the compendium that I collected on the "success
stories" on the application of semiempirical methods My
focus was on commercial or "real world" applications, and
I received quite a few entries that didn't fit into this
categorization. I am surprised at the paucity of such data,
but as I said in my original posting, a great deal of this
is proprietary (I hope!). I would like to continue to expand
this database so please pass along any further items you have.
Thanks to all those who responded and to Clarke Earley here at
UMKC for helping with the summaries. Enjoy...
Andy
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DR. ANDREW HOLDER
Assistant Professor of Computational/Organic Chemistry
Department of Chemistry || BITNET Addr: AHOLDER (- at -)
UMKCVAX1
University of Missouri - Kansas City || Internet Addr: aholder (- at -)
vax1.umkc.edu
Spencer Chemistry, Room 502 || Phone Number: (816) 235-2293
Kansas City, Missouri 64110 || FAX Number: (816) 235-1717
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1. Boyd, D. B.; Eigenbrot, C.; Indelicato, J. M.; Miller, M. J.;
Pasini, C. E.; Woulfe, S. R. J. Med. Chem. 1987, 30, 528.
In the search for new beta-lactam antibiotics (penicillins fall
in this class of compounds), it was found that sulfur-based
drugs (thiamazins) displayed no activity while the traditional
oxygen-based drugs (oxamazins) were useful. The explanation
of this surprising behavior was partially explained by
semiempirical calculations, which indicated that the structure
of the inactive drugs results in a poor fit with the "active
site". These calculations (which utilized the AM1, MNDO, and
MINDO/3 methods) were also able to show that several other
factors were probably not important, which lowers the likelihood
that potentially useful drugs will be eliminated without
consideration.
2. Boyd, D. B. in Successes of Computer-Assisted Molecular Design;
1990; pp 362.
Myclobutanil is a broad spectrum, agrochemical fungicide. After
narrowing the possible types of compounds that appeared useful
by field testing, differences between the activity of these
molecules were correlated with a number of molecular properties,
including an analysis of molecular charges calculated using the
semiempirical MNDO method. The eventual development of
myclobutanil was credited as a direct result of this analysis.
3. Earley, C. W. Inorg. Chem. 1992, in press.
It is estimated that over 400,000 tons of zeolites are used
annually, primarily in petroleum refining processes. Since
these are solid state materials, both experimental and
theoretical investigations are quite difficult. However,
it has been shown that the results of quantum mechanical
calculations on isolated molecules can be successfully
applied to enhance understanding some of the properties of these
solid-state materials. In this case, AM1 calculations on
molecules containing as few as two or three silicon centers
can be used to explain one of the basic structural features
of these molecules, and semiempirical calculations on larger
molecules have been used to determine the most acidic sites.
4. Holder, A. J.; Upadrashta, S. J. Pharm. Sci. 1992, in press.
The antipsoriatic drug anthralin has been in use for over
60 years. This AM1 study explains some of the properties
that make the drug active and suggests further directions
for research.
5. Kador, P. F.; Sharpless, N. E. Molec. Pharm. 1983, 24, 521.
Clinical trials of an aldose reductase inhibitor suggests that
these types of compounds can prevent certain eye problems
(cataract formation and corneal re-epithelialization) in
diabetic patients. Clinical studies indicate that no
"universally potent" inhibitor exists, emphasizing the
need to find new drugs of this type. Comparison of the
activities of several of these drugs with results of quantum
mechanical calculations (energies of lowest unoccupied
molecular orbitals and atomic charges) showed strong
correlations, which aided in prediction of the minimal
requirements for an active drug.
6. Kehl, H.; Holder, A. J. J. Pharm. Sci. 1991, 80, 139.
GABA (gamma-aminobutyric acid) is a mediator of the
central nervous system and has been implicated as a
contributor in chemically-induced depression. A
theoretical study using the AM1 method on GABA and
two derivatives of this compound was able to show
that one of these derivatives is more closely related
to the parent system than the second. This result
is in agreement with the actual experimental results.
7. Ripka, W. C.; Sipio, W. J.; Blaney, J. M. Lect. Heterocyc. Chem.
1987, IX, S95.
The Phospholiphase A2 enzyme is thought to be involved in
the breakdown of phospholipids, important components in
living systems. This study was undertaken to show that
theoretical methods can be successfully applied to drug
design. Analysis of the geometries of a number of proteins
suggested one key structural component. Quantum mechanical
calculations not only supported these findings, but were
also able to offer a simple explanation for this phenomenon.
8. Szarek, W. A.; Smith, V. H.; Woods, R. J. J. Am. Chem. Soc. 1990,
112, 4732.
Quantum mechanical calculations on a number of simple sugars
provided an explanation of the relative sweetness of these
compounds. Analysis of the structural features observed in
the calculated geometries of these compounds suggests that a
previously neglected feature of these molecules may be impor-
tant in determining "sweetness".
9. Wasielewski, M. R.; Johnson, D. G.; Bradford, E. G.; Kispert,
L. D. J. Chem. Phys. 1989, 91, 6691.
Caroteniods are light-gathering agents in the pigments of eyes.
In order to understand the efficiency of these compounds in
transferring light energy, a theoretical study using the AM1
method was performed. The explanation for the high efficiency
of this process obtained from these calculations was in
agreement with the results of experimental studies.
10. Culberson, J. C.; Walters, D. E. 199th National Meeting of the
American Chemical Society, 1990, 214.
Muller, G. W.; Walters, D. E.; DuBois, G. E. J. Med. Chem. 1
992, 35, 740.
Hallinan, E. A.; Walters, D. E.; DuBois, G. E.; Mazur, R. H.;
Muller, G. W. J. Agric. Food. Chem. 1991, 39, 1836.
These three references describe cxomputational work on defining
the sweet receptor and investigating compounds to interact with
it more advantageously.