Docking, ADME toxicity analysis of Alprazolam derivatives as potent anxiolytic drug

Abstract

Abstract GABAergic, Gamma Amino Butyric Acid A (GABAA) receptors are permeable to the chloride ion gated channel, on hyperexcitability alters the ions gradients and leads to anxiety-related diseases. The study aims to elucidate the potent inhibitory ligands of alprazolam and their analogues, those retrieved from the PubChem database as ligands against the GABAA receptor as a target to reduce the daily dose administration. In-silico methods like molecular docking were performed using docking tool, Autodock and Autodock vina version 4.2, Absorption Digestion Metabolism Excretion toxicity through Swiss ADME and OSIRIS online tools to find potent lead ligand and predicting drug-likeness. Molecular docking showed that three compounds A3, A8, and A9 had significant binding affinities (-8.0 to -8.2 kcal/mol) to the target. The ADME toxicity study showed three ligands (PubChem ID: 1032832, 12632256, and 12632257) with good binding affinity, obeyed Lipinski’s rule of five. A8 chemical compound can cross the blood-brain barrier out of three ligands, A3 and A9 ligands remained in the gastrointestinal region, which is represented in the BOILED-Egg model. The study revealed one potent antagonist of GABAA receptors, namely 8-chloro-1,4-dimethyl-6-phenyl-4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine, these can be further exploited for upon molecular dynamics study followed by wet-lab studies perhaps used for the therapeutics as an anxiolytic drug.