RESUMO
Due to the importance of benzodiazepine drugs in clinical practice, such as the treatment of anxiety disorders, depression, and insomnia and the side effects of classical benzodiazepines, the study of new benzodiazepine agonists has received much attentions. In this work, we used in silico methods to explore the molecular mechanism of 1,2,4-triazolo [1,5-a] pyrimidinone derivatives in the modulation of α1ß2γ2 subtype of GABAA receptor. To this aim, molecular docking, molecular dynamics simulation (MD), post-MD analysis, binding free energy calculation, and prediction of ADME properties were performed. Results showed that all new compounds have a better binding affinity for the Benzodiazepine (BZD) site of the receptor than diazepam and compound 4c had the highest affinity among them. Moreover, a good agreement was observed between the calculated ΔGbinding and experimental IC50 values. Also, we noticed that residues in loop regions (particularly loop C and D-F in α1 and γ2 subunits, respectively) forming BZD binding site, take part in forming several H-bonds between the agonists and the receptor. Ser205, Thr207, Tyr160, and His102 of α1 subunit and Thr207 of γ2 subunit are mainly involved in forming H-bonds. Also, the orientation of agonists in the BZD binding site leads to π-π interactions with hydrophobic residues in loops A-F. Based on the DCCM analysis, the correlated motions in the γ2 subunit residues are greater than those of α1 subunit residues. Further, predicted ADME results indicated that all agonists meet the criteria. The triplicate MD simulation showed the reproducibility of the results and strengthened the study. Our results provide a comprehensive insight into the receptor-agonist interactions and clues for designing future BZD agonists.