In silico assessment of benzyl C-analogues of dapagliflozin as potential SGLT2 inhibitors for type 2 diabetes.

Type 2 diabetes (T2D) is a chronic metabolic disorder managed by drugs like the sodium-glucose cotransporter-2 (SGLT2) inhibitor dapagliflozin. Due to associated adverse effects, the search for safer benzyl C-analogues is warranted. In this in silico study, nine novel analogues (A1-A9) and a reference compound (A10) were evaluated as potential SGLT2 inhibitors. All compounds satisfied drug-likeness criteria and exhibited favourable ADMET profiles, with five classified as toxicity class V. Molecular docking and 300ns molecular dynamics (MD) simulations identified A1 as the most promising candidate. A1 consistently demonstrated the most favourable binding free energy (MM/GBSA: -152.86±16.27kJ/mol) compared to A10 (-130.06±11.63kJ/mol), driven by van der Waals and electrostatic interactions. Furthermore, A1 induced superior dynamic stability, characterized by lower RMSD (0.268±0.023nm), reduced SASA (236.93±3.65nm2), and restricted collective motions (PCA). Crucially, the computational ranking strongly correlated with available in vitro data, where A1 exhibited the highest inhibitory potency (IC50=0.64nM). These combined findings suggest that compound A1 is a promising candidate, which warrants further experimental validation for T2D treatment.