Unveiling Naringenin as a dual SGLT2–FimH inhibitor: An in silico docking and molecular dynamics investigation

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are effective in type 2 diabetes management but can predispose patients to urinary tract infections (UTIs). Uropathogenic Escherichia coli use FimH adhesin to colonize the urinary tract. Natural compounds such as Naringenin, a citrus flavonoid, may offer safer multitargeted alternatives by inhibiting both SGLT2 and FimH. This study evaluated Naringenin as a potential dual inhibitor of SGLT2 and FimH, comparing its binding behavior with the standard SGLT2 inhibitor Dapagliflozin and the FimH antagonist Heptyl-α-D-mannopyranoside (HADMP). In silico analyses combining molecular docking, molecular dynamics (MD) simulations, and MM-GBSA binding free energy calculations were conducted. Structural stability was assessed using RMSD, RMSF, radius of gyration, and hydrogen bond profiles. Toxicity was predicted using ProTox-3.0. Naringenin showed favorable binding with both targets, stabilizing SGLT2 comparably to Dapagliflozin and FimH comparably to HADMP. MD and MM-GBSA analyses highlighted consistent affinity supported by van der Waals and lipophilic interactions. The predicted toxicity indicated a potential cytotoxicity flag for Naringenin, warranting experimental validation. Naringenin demonstrates promising dual inhibitory activity against SGLT2 and FimH, suggesting a natural, multitarget alternative for managing diabetes while reducing UTI risk. Experimental studies are needed to confirm these computational insights.