A Combined Virtual Screening 2D and 3D QSAR Methodology for the Selection of New Anticonvulsant Candidates from Natural Product Library

GAVERNET LUCIANA; TALEVI ALAN; CASTRO EDUARDO A.; BRUNO BLANCH LUIS E.

QSAR & Combinatorial Science

Año: 2008 vol. 27 p. 1120 - 1129

A virtual screening methodology combining a discriminant function (df)based on Dragon2D-descriptors, general ADME filters, and a pharmacophore identified through superpositionof rigid analogs was applied in order to identify new anticonvulsant agents among10903 natural products. Fifty-six compounds were selected from the application of this df,Lipinski´s rule-of-five and other criteria for prediction of oral bioavailability, and theoptimal value of log P for a compound to diffuse passively through the blood – brainbarrier. Seven of these compounds were removed because they did not belong todescriptor space defined by the training set. The remaining 49 compounds were fitted tothe pharmacophore structural constrains, selecting 7 structures with RMS distance valuebelow 0.2. Systematic conformational analysis was performed to find the global minimumconformation, using the PM3 base included in Hyperchem 6.03. The global minimumconformations were further refined at a 6-31G** level with Gaussian 03. Restrictedoptimization was then performed to determine the energy difference between the energyminimum conformation and the active conformation defined by the pharmacophore,retaining those structures whose energy differences were below 7 kcal/mol. Four newpotential anticonvulsants which fulfill the df and the pharmacophore requisites wereselected. One of these structures, 2-(4,6-dimethyl-1-benzofuran-3-yl)acetic acid, wasacquired and assayed in the MES and Rotorod tests, confirming anticonvulsant activity inmice at 30 and 100 mg/kg (0.5 and 4 h, i.p.)and absence of neurotoxicity at the testeddoses.