Design of novel benzimidazole derivatives as potential a-amylase inhibitors using QSAR, pharmacokinetics, molecular docking, and molecular dynamics simulation studies

In the present study, a quantitative relationship between the biological inhibitory activity of alpha-amylase and molecular structures of novel benzimidazole derivatives is analyzed in silico. The best QSAR model screened via MLR technique indicated that the exact mass, topological diameter and numerical rotational bonding structural properties of benzimidazole derivatives highly affect the bioactivity of these compounds against a-amylase. Based on the structural properties identified via linear QSAR model favorable for improving pIC50 of benzimidazole derivatives, fourteen new molecules bearing benzimidazole radicals were designed and their biological inhibitory activity against a-amylase was improved. QSAR model predictions showed that the designed molecules exhibited a higher potential biological level activity IC50 than acarbose used in positive control (IC50= 1.46 mu M). Screening of drug-like properties, pharmacokinetics and toxicity of the proposed molecules led to select three molecules as candidates for use as drug aid to ingest starch and glycogen. As a result, using molecular docking simulations, the docking poses of the three molecules inside the a-amylase receptor pocket (PDB code: 1HNY) were predicted. Also, the most important potential interactions between the active amino acid sites in a-amylase protein pocket and the proposed drug molecules were described. The obtained hypotheses regarding the stability of the proposed molecules inside a-amylase pocket were validated by carrying out molecular dynamic simulations in aqueous background similar to the ones of proteins. The DM results confirmed the optimal stability of the a-amylase backbone with the drug molecules proposed in this computational investigation.

Automated summary

This study explores the relationship between the molecular structures of novel benzimidazole derivatives and their inhibitory activity against alpha-amylase. The findings suggest that the exact mass, topological diameter, and rotational bonding structural properties of these derivatives significantly affect their bioactivity. By designing molecules with favorable structural properties, the biological inhibitory activity against alpha-amylase was improved. Three molecules were selected as potential drug candidates for aiding in starch and glycogen digestion based on drug-like properties, pharmacokinetics, and toxicity screenings. Molecular docking simulations and molecular dynamic simulations validated the stability and interactions between the proposed molecules and the alpha-amylase protein.