QUANTUM-CHEMISTRY IN QSAR - ANTICONVULSIVANT ACTIVITY OF VPA DERIVATIVES

A QSAR analysis of a series of Valproic Acid (vpa) derivatives is give n, which shows the importance of hydrophobic and electronic effects as determinants of the anticonvulsivant activity. The statistical analys is allows one to infer that the electron acceptor capability of the ca rboxylic carbon atom may guide electrostatic interactions of the molec ules with the receptor site, in those cases where the lipophilic requi rements are satisfied. Both the anticonvulsivant activity and the calc ulated lipophilic parameters (log P values) are taken from the literat ure, whereas the electronic descriptors result from Intermediate Negle ct of Differential Overlap calculations at the Configuration interacti on 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 conformat ional analysis is based on AM1 calculations. (C) 1995 John Wiley & Son s, Inc.