A Novel Approach for the Identification of Selective Anticonvulsants Based on Differential Molecular Properties for TBPS Displacement and Anticonvulsant Activity: An Integrated QSAR Modelling

Abstract

AbstractIn order to gain insight into the structural and molecular requirements influencing the anticonvulsant activity against Pentylenetetrazole (PTZ)‐induced seizures and [35S] tert‐Butyl‐bicyclophosphorothionate (TBPS) displacement property (a measure of binding to GABAA receptor), Quantitative Structure–Activity Relationship (QSAR) studies have been performed on a series of congeneric anticonvulsant agents proposed to act by binding to the lactone site of the GABAA receptor. The aim of this work was to identify and analyse the various functionalities, which determine the TBPS displacement property and anticonvulsant activity by correlating with various molecular descriptors. Statistical techniques like Principal Component Analysis (PCA), Partial Least Squares (PLS), Multiple Linear Regression (MLR) and Genetic Function Approximation (GFA) were applied to identify the structural and physicochemical requirements for TBPS displacement property and anticonvulsant activity. The generated equations were statistically validated using leave‐one‐out cross‐validation technique and randomization. The best models were also validated by prediction of activity of compounds, not used for the development of QSAR models. The results from reasonably good QSAR models (statistically validated) clearly indicated that TBPS displacement property and the anticonvulsant activity are defined by different molecular parameters. Based on this finding, a novel approach is proposed, using integrated QSAR modelling, for the identification of potential and selective anticonvulsant agents.