A Structure‐based QSAR and Docking Study on Imidazo[1,5‐a][1,2,4]‐triazolo[1,5‐d][1,4,]benzodiazepines as Selective GABAAα5 Inverse Agonists

Abstract

As three-dimensional (3D) structure of the GABA(A) α5 was not determined, the crystal structure of 2Vl0E at 3.3 Å resolution which is a ligand-gated K(+) channel was used as a template in homology modeling, and the result was used in molecular dynamic simulation for obtaining its conformation in a water sphere. The resulted conformation of the receptor was used for docking with the most potent of imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4,] benzodiazepines drugs to find out binding sites and consequently the types of the interaction between the drugs and receptor. The results showed that π-π interaction of the drugs with three phenylalanine and tyrosine residues plays an important role in determining the potency of the inhibitors. The obtained information relating to the binding sites of the receptor was utilized for docking all the drugs into the receptor and find out optimized conformation for each drug, used in structure-based quantitative structure-activity relationship (QSAR) model for calculation of descriptors. Then, selected descriptors were related to the binding affinity and selectivity of the drugs using multiple linear regression and least squares-support vector regression. Finally, the results of target- and ligand-based QSAR models were compared, resulted the superiority of the structure-based QSAR to the ligand-based model.