Quantitative structure-activity relationship and molecular docking studies of a series of quinazolinonyl analogues as inhibitors of gamma amino butyric acid aminotransferase

Abstract

Quantitative structure-activity relationship and molecular docking studies were carried out on a series of quinazolinonyl analogues as anticonvulsant inhibitors. Density Functional Theory (DFT) quantum chemical calculation method was used to find the optimized geometry of the anticonvulsants inhibitors. Four types of molecular descriptors were used to derive a quantitative relation between anticonvulsant activity and structural properties. The relevant molecular descriptors were selected by Genetic Function Algorithm (GFA). The best model was validated and found to be statistically significant with squared correlation coefficient (R²) of 0.934, adjusted squared correlation coefficient (R²_adj) value of 0.912, Leave one out (LOO) cross validation coefficient (Q²) value of 0.8695 and the external validation (R²_pred) of 0.72. Docking analysis revealed that the best compound with the docking scores of −9.5 kcal/mol formed hydrophobic interaction and H-bonding with amino acid residues of gamma aminobutyric acid aminotransferase (GABA_AT). This research has shown that the binding affinity generated was found to be better than the commercially sold anti-epilepsy drug, vigabatrin. Also, it was found to be better than the one reported by other researcher. Our QSAR model and molecular docking results corroborate with each other and propose the directions for the design of new inhibitors with better activity against GABA_AT. The present study will help in rational drug design and synthesis of new selective GABA_AT inhibitors with predetermined affinity and activity and provides valuable information for the understanding of interactions between GABA_AT and the anticonvulsants inhibitors.