Exploring the potential of 2-arylbenzimidazole scaffolds as novel α-amylase inhibitors: QSAR, molecular docking, simulation and pharmacokinetic studies.

Abstract

Previous studies have shown that 2-arylbenzimidazole derivatives have a strong anti-diabetic effect. To further explore this potential, we develop new analogues of the compound using ligand-based drug design and tested their inhibitory and binding properties through QSAR analyses, molecular docking, dynamic simulations and pharmacokinetic studies. By using quantitative structure activity relationship and ligand-based modification, a highly precise predictive model and design of potent compounds was developed from the derivatives of 2-arylbenzimidazoles. Molecular docking and simulation studies were then conducted to identify the optimal binding poses and pharmacokinetic profiles of the newly generated therapeutic drugs. DFT was employed to optimize the chemical structures of 2-arylbenzimidazole derivatives using B3LYP/6-31G* as the basis set. The model with the highest R2trng set, R2adj, Q2cv, and R2test sets (0.926, 0.912, 0.903, and 0.709 respectively) was chosen to predict the inhibitory activities of the derivatives. Five analogues designed using ligand-based strategy had higher activity than the hit molecule. Additionally, the designed molecules had more favorable MolDock scores than the hit molecule and acarbose and simulation studies confirm on their stability and binding affinities towards the protein. The ADME and druglikeness properties of the analogues indicated that they are safe to consume orally and have a high potential for total clearance. The results of this study showed that the suggested analogues could act as α-amylase inhibitors, which could be used as a basis for the creation of new drugs to treat type 2 diabetes mellitus.