INIFTA   05425
INSTITUTO DE INVESTIGACIONES FISICO-QUIMICAS TEORICAS Y APLICADAS
Unidad Ejecutora - UE
artículos
Título:
A combined virtual screening 2D and 3D QSAR methodology for the selection of new anticonvulsant candidates from a natural product library
Autor/es:
A. TALEVI; L. GAVERNET; E.A. CASTRO; L. BRUNO BLANCH
Revista:
QSAR & Combinatorial Science
Referencias:
Año: 2007
Resumen:
Abstract
A virtual screening methodology combining a discriminant function based on Dragon
2D-descriptors, general ADME filters and a pharmacophore identified through
superposition of rigid analogs was applied in order to identify new anticonvulsant
agents among 10,903 natural products. 56 compounds were selected from the
application of this discriminant function, Lipisnki´s rule-of-five and other criteria for
prediction of oral bioavailability, and the optimal value of log P for a compound to
diffuse passively through the blood-brain barrier. 7 of these compounds were removed
because they did not belong to descriptor space defined by the training set. The
remaining 49 compounds were fitted to the pharmacophore structural constrains,
selecting 7 structures with RMS distance value below 0.2. Systematic conformational
analysis was performed to find the global minimum conformation, using the PM3 base
included in Hyperchem 6.03. The global minimum conformations were further refined
at a 6-31G** level with Gaussian 03. Restricted optimization was then performed to
determine the energy difference between the energy minimum conformation and the
active conformation defined by the pharmacophore, retaining those structures whose
energy difference were below 7 kcal/mol. 4 new potential anticonvulsants which fulfill
the discriminant function and the pharmacophore requisites were selected. One of these
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Wiley-VCH
QSAR & Combinatorial Science
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For Review Only
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structures, 2-(4,6-dimethyl-1-benzofuran-3-yl)acetic acid, was acquired and assayed in
the MES and Rotorod tests, confirming anticonvulsant activity in mice at 30 and 100
mg/kg (0.5 and 4 hours, i.p.) and absence of neurotoxicity at the tested doses.