Abstract
Anxiety is the most common neurological disorder and results in cognitive, emotional, and somatic behavioral changes. Anxiety may invoke an unpleasant feeling that is strongly associated with apprehension, fear, and disturbance of daily routine life activities. GABA acts as an inhibitory neurotransmitter within the central nervous system, and a decrease in its levels can result in anxiety. Therefore, GABA-A receptor proteins (PDB ID: 4COF) are suitable targets for drug design. Lorazepam is a commonly used drug for the treatment of short-term anxiety. However, Lorazepam causes serious side effects both physically and mentally during treatment for patients. To alleviate the serious side effects of Lorazepam, in this work, in silico studies based on modern artificial intelligence (AI)-based virtual screening were carried out with a series of computational chemistry methods, such as molecular docking (MD), molecular dynamics simulation (MDS) and quantitative structure–activity relationships (QSAR). Initially, using the MolAICal tool, compounds similar to Lorazepam were generated (M1-M12), and based on drug likeliness, 9 compounds were selected (M1, M4-M7, M9-M12). Then, molecular docking was carried out to analyze and visualize their binding scores with the 4COF protein structure. Compound M12 has a greater binding affinity (i.e., a lower binding energy of -8.276 kcal/mol) than Lorazepam. Its applicability was ascertained via QSAR analysis. A molecular dynamics study of M12 and that of Lorazepam showed that M12 has very good binding to the protein 4COF through multiple H-bond interactions, as more than 100% of the simulation times with the ASP 43 residue and 98% of the simulation times with the GLU155 residue. Various protein‒ligand interactions that lasted more than 48% of the simulation time in the selected trajectory were considered. Analysis of these parameters demonstrated the stable binding of M12 within the binding pocket of 4COF, and M12 had more interactions; hence, M12 was proven to be an alternative drug for treating anxiety with high efficacy.