Design, 3D-QSAR, molecular docking, MD simulations, ADME/Tox properties and DFT study of benzimidazole derivatives as promising α-glucosidase inhibitors

Acarbose and miglitol are two distinct alpha-glucosidase inhibitors that are frequently used to manage diabetes mellitus. Unfortunately, the clinical usage of these medications comes with a number of undesirable side effects. Therefore, development of safer and potent alpha-glucosidase inhibitor became more necessary. For this reason, a set of 20 benzimidazole-based oxadiazole molecules was addressed using the three-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) approach. Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) using steric (S), electrostatic (E) and hydrogen bond donor (D) models showed good statistical outcomes as Q2 (0.600 and 0.616 respectively) and R2 (0.958 and 0.928 respectively). The developed models were then validated for their external ability; the R2test values were 0.85 and 0.627, respectively. The CoMFA and CoMSIA/SED contour maps helped identify key regions influencing alpha-glucosidase inhibitory activity, leading to the design of four new benzimidazole-based oxadiazole inhibitors with strong predicted activity. The new recommended compounds confirmed promising consequences in the preliminary in silico ADME/Tox prediction. Molecular docking results showed good interactions of compounds M1 and M2 in the active site of the alpha-glucosidase receptor, and their stability was studied using molecular dynamics simulations throughout 200 ns. The reactivity and stability of compounds M1 and M2 were assessed using the DFT approach, suggesting that these compounds have strong inhibitory potential and may serve as effective anti-diabetic agents, warranting further experimental investigation.