Quantum chemistry inQSAR: Anticonvulsivant activity of VPA derivatives

Abstract

A QSAR analysis of a series of Valproic Acid (vpa) derivatives is given, which shows the importance of hydrophobic and electronic effects as determinants of the anticonvulsivant activity. The statistical analysis allows one to infer that the electron acceptor capability of the carboxylic carbon atom may guide electrostatic interactions of the molecules with the receptor site, in those cases where the lipophilic requirements are satisfied. Both the anticonvulsivant activity and the calculated lipophilic parameters (log P values) are taken from the literature, whereas the electronic descriptors result from Intermediate Neglect of Differential Overlap calculations at the Configuration Interaction level, (INDO/S-CI parametrization), for the most stable conformers of each derivative. The protein environment is modeled as a dielectric continuum in a Self-Consistent Reaction Field approach. The conformational analysis is based on AMI calculations. © 1995 John Wiley & Sons, Inc.