Novel α‐glucosidase Inhibitors Designed as Type 2 Diabetes Drugs by QSAR, Molecular Docking and Molecular Dynamics Simulation Methods

Diabetes mellitus is a globally prevalent disease of significant concern. Alpha‐glucosidase has emerged as a prominent target for the treatment of type 2 diabetes. In this study, 39 α‐glucosidase inhibitors (AGIs) of tetrahydrobenzo[b]thiophene‐2‐ylurea derivatives to establish a stable and valid Topomer CoMFA model, with a cross‐validation coefficient (q²) of 0.766 and a non‐cross‐validation coefficient (r²) of 0.960. Subsequently, the ZINC15 database was used to screen the fragments, based on which 13 novel inhibitor molecules with theoretically potentially high activity were designed. Molecular docking and molecular dynamics simulations to understand the binding status of the inhibitor molecules to the target proteins showed that amino acids ASP215, GLN279 and ARG442 may form hydrogen bonds with the ligands and therefore enhance the inhibitory effect of the small molecules. Additionally, MM/PBSA calculations suggest that the newly designed molecules demonstrate more stable binding modes, and these newly designed molecules showed good ADMET properties with potential as AGIs. The findings would provide valuable guidance and a theoretical foundation for the design and development of novel AGIs.