Drug repurposing for diabetes mellitus: In silico and in vitro investigation of DrugBank database for α-glucosidase inhibitors

Abstract

The process of developing novel compounds/drugs is arduous, time-intensive, and financially burdensome, characterized by a notably low success rate and relatively high attrition rates. To alleviate these challenges, compound/drug repositioning strategies are employed to predict potential therapeutic effects for DrugBankapproved compounds across various diseases. In this study, we devised a computational and enzyme inhibitory mechanistic approach to identify promising compounds from the pool of DrugBank-approved substances targeting Diabetes Mellitus (DM). Molecular docking analyses were employed to validate the binding interaction patterns and conformations of the screened compounds within the active site of alpha-glucosidase. Notably, Asp352 and Glu277 participated in interactions within the alpha-glucosidase-ligand complexes, mediated by conventional hydrogen bonding and van der Waals forces, respectively. The stability of the docked complexes (alpha-glucosidasecompounds) was scrutinized through Molecular Dynamics (MD) simulations. Subsequent in vitro analyses assessed the therapeutic potential of the repositioned compounds against alpha-glucosidase. Kinetic studies revealed that "Forodesine" exhibited a lower IC50 (0.24 +/- 0.04 mM) compared to the control, and its inhibitory pattern corresponds to that of competitive inhibitors. In-depth in silico secondary structure content analysis detailed the interactions between Forodesine and alpha-glucosidase, unveiling significant alterations in enzyme conformation upon binding, impacting its catalytic activity. Overall, our findings underscore the potential of Forodesine as a promising candidate for DM treatment through alpha-glucosidase inhibition. Further validation through in vitro and in vivo studies is imperative to confirm the therapeutic benefits of Forodesine in conformational diseases such as DM.