Application of Molecular Topology in Descriptor-based Virtual Screening for the Discovery of New Anticonvulsant Agents

TALEVI ALAN; BELLERA CAROLINA LETICIA; CASTRO EDUARDO A.; BRUNO-BLANCH LUIS E.

Estambul

Simposio; XIXth International Symposium on Medicinal Chemistry; 2006

European Federation for Medicinal Chemistry - Turkish Association of Pharmaceutical and Medicinal Chemistry

From a training set made of clinical anticonvulsant drugs whose mechanism of action involves sodium channels blockade, several topological models for recognition of anticonvulsant activity were generated. The models were validated through randomization test, leave-one-out cross-validation and external validation. The model that performed best in the validation steps was applied in the virtual screening of a library of 500,000 compounds. These structures were analyzed to assure normal distribution regarding the parametres included in Lipinski´s "rule of five": molecular weight, number of H bond donors, number of H bond acceptors and log P; in this way we verified both the structural diversity and the drug-like properties of the screened compounds. Some of the drugs selected in the virtual screening were bioassayed in the Maximal Electroshock test with good results, which arises as strong evidence of the efficacy of the employed methdology.