Abstract

IN SILICO ANALYSIS AND DESIGN OF DIAZEPAM DERIVATIVES FOR ENHANCED GABAA RECEPTOR MODULATION

Shivkanya S. Khandebharad* and Seema P. Rathod

ABSTRACT

In this research, we employed various computational techniques, including Quantitative Structure-Activity Relationship (QSAR) analysis, molecular docking, and molecular dynamics (MD) simulations, to investigate a dataset of [3H] diazepam derivatives. Our primary aim was to elucidate the structural requirements that enhance the interaction of benzodiazepine drugs with the GABAA receptor α1β2γ2 subtype, and to understand the allosteric modulation mechanism of GABA binding. The molecular docking results identified proflazepam and Ro12-6377 as the optimal modulators for the four binding sites on the receptor. Subsequent MD simulations were conducted to evaluate the stability of these complexes, confirming that the modulators significantly influenced the residues lining the chloride channels. In silico pharmacokinetics and drug-likeness profiles were assessed to evaluate the potential of methylated derivatives. Twoconformers were used to classify flavones: Conformer A, represented by 5'-bromo-2'-hydroxy-6- methylflavone, with the 2-phenyl group interacting with 114TYR, and Conformer B, represented by apigenin, with the flavone nucleus surrounded by 114TYR.

Keywords: QSAR, GABA receptor, Diazepam, Molecular Simulation, 114TYR.