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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. August 2003, Volume 2, Number 8, 511-526 |
Three-Dimensional Molecular Field Analyses of Agonists for
Tyramine Receptor which Inhibit Sex-Pheromone Production in
Plodia interpunctella
Akinori Hirashima, Tomohiko Eiraku, Eiichi Kuwano, and Morifusa Eto
Internet Electron. J. Mol. Des. 2003, 2, 511-526
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Abstract:
In drug discovery, it is common to have measured activity data
for a set of compounds acting upon a particular protein but not to
have knowledge of the three-dimensional structure of the protein
active site. In the absence of such three-dimensional information,
one can attempt to build a hypothetical model of the receptor site
that can provide insight about receptor-site characteristics. Such
an analysis is known as a molecular-field analysis (MFA), which
provides compact and quantitative descriptors which capture
three-dimensional information about a putative receptor site.
Several compounds were tested for inhibitory specificity using a
modified radiochemical bioassay to monitor de novo pheromone
production in Plodia interpunctella. All computational
experiments were conducted with Cerius2 3.8 quantitative
structure-activity relationship (QSAR) environment on a Silicon
Graphics O2, running under the IRIX 6.5 operating system.
Multiple conformations of each molecule were generated using
the Boltzmann jump as a conformational search method. An
MFA was generated from the 28 agonists for tyramine (TA)
receptor which inhibited sex-pheromone production in
P. interpunctella. 2-(Substituted benzylthio)-2-oxazoline
(SBO) 2 had the highest potency, followed by SBO derivative
6 and 3,
substituted with 3-CH3, 4-CH3,
and 3-CF3, respectively, in
inhibition of de novo pheromone production. The predictive
character of the QSAR was further assessed using 4 agonists for
TA receptor as test molecules. The result may imply that the
process of calculating an MFA treats the structures reasonably.
The MFA could provide useful information in the
characterization and differentiation of TA receptor. It may help
to point the way towards developing extremely potent and
relatively specific TA ligands, leading to potential insecticides,
although further research on the comparison of the 3D QSAR is
necessary.
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