Design of new α-glucosidase inhibitors through a combination of 3D-QSAR, ADMET screening, molecular docking, molecular dynamics simulations and quantum studies

Diabetes mellitus is a chronic and non-infectious metabolic disorder caused by insufficient insulin secretion. This study investigated a set of thirty-one 4-amino-1,2,4-triazole derivatives, experimentally evaluated for their α-glucosidase activity against diabetes mellitus, using the three-dimensional quantitative structure–activity relationship (3D-QSAR) approach. The recommended CoMFA and CoMSIA/EHA models showed good predictive ability, manifested by high R2 values and important Q2 values. The molecular structural features offered by the CoMFA and CoMSIA/EHA contour maps had a significant impact on the determination of appropriate groups to enhance activity. Hence, four new 4-amino-1,2,4-triazole inhibitors were proposed and designed with good predicted α-glucosidase activity. The pharmacological and ADME-Tox properties of the four recommended molecules were predicted and examined. Molecular docking studied the interaction modes between the targeted receptor and 4-amino-1,2,4-triazole derivatives; it showed good stability for the new title molecule M1. Furthermore, molecular dynamics simulation at 100 ns and MM/PBSA approach results demonstrated an acceptable stability and the interactive force of the compound M1. Finally, the most nucleophilic and electrophilic centers of the compounds C25 and M1 were determined using quantum analysis. The current work encourages further experimental and scientific research on M1 molecule as a potent α-glucosidase inhibitor.