Molecular docking, dynamics, and drug-likeness studies of alprazolam derivatives as a potent anxiolytic drug against GABAA receptors

GABAA receptors exhibit permeability to the chloride ion-gated channel, and an increase in excitability disrupts the ion gradients, hence contributing to the development of anxiety-related disorders. This study aims to repurpose potent inhibitors of alprazolam analogs, which were obtained from the PubChem database. These ligands are being investigated for their binding ability to the GABAA receptor. We employed molecular docking through Autodock vina V.4.2 software. The Swiss ADME server was utilized to assess the drug-likeness of the ligands. MDS was conducted using the iMODS platform. Compounds A3, A8, and A9 exhibited a notable binding score range of -8.0 to -8.4 kcal/mol-1 with GABAA protein. The drug-likeness analysis revealed that 3 ligands had compliance with Lipinski's RO5. Moreover, the A8 compound can traverse the BBB. In contrast, the A3 and A9 ligands remain localized in the GI region. The MDS of the GABAA receptor with the A8 molecule exhibited higher stability than alprazolam. The current investigation unveiled a highly effective antagonist of GABAA receptors, specifically A8 - 8-chloro-1,4-dimethyl-6-phenyl-4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine. This compound holds potential for future wet-lab experiments, perhaps leading to its utilization in therapeutic applications as an anxiolytic medication.