DFT-based QSAR studies and Molecular Docking of 1-Phenylcyclohexylamine Analogues as anticonvulsant of NMDA Receptor

Abstract

The phencyclidine (PCP) and their analogues have been reported to exhibit inhibitory activities toward the N-methyl-D-aspartate receptor (NMDAR). To discover the QSAR between structure of PCP derivatives and Ki activities we have used density functional theory (DFT) to generate quantum descriptors, multiple regression linear (MLR) method was applied to establish QSAR model, and an artificial neural network (ANN), considering the relevant descriptors obtained with the MLR method is explored, a correlation coefficient of R_ANN = 0.912 was obtained with 6-4-1 ANN model. This model is tested by using a cross-validation method with the LOO procedure (R_CV = 0.841). To study the configuration impact on activity, we proceed to the Molecular Docking of four configurations, two configurations of compound have (Ki = 502 nM) and two configurations of compound have (Ki = 1200nM). The phenyl group, when placed in an equatorial position in cis9e, a configuration of the less active compound, does not form π-sigma interaction. The superimposition of this configuration with trans7e reveals that the phenyl group of cis9e configuration is shifted from the binding site compared to trans7e which forms an interaction π-sigma throughout its phenyl group with ARG B: 894. So, we could claim that the cis9e is the configuration adopted by compound having (Ki = 502 nM).