Design principles for natural SGLT2 modulators from multi-scale computation

Abstract Human sodium-glucose cotransporter 2 (hSGLT2) is a membrane-embedded renal transporter and an established therapeutic target for type 2 diabetes. Hyperoside, myricetin, cyanidin-3-O-glucoside and isoliquiritigenin were investigated as a chemically diverse panel of natural scaffolds using a multi-scale computational workflow combining redocking-validated molecular docking, reconstruction of an unresolved transporter segment, molecular dynamics (MD) in an explicit POPC bilayer, molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) calculations, principal component and free-energy landscape analyses and density functional theory (DFT). The membrane simulations preserved the global hSGLT2 fold while revealing distinct ligand-dependent binding behaviours. Myricetin and cyanidin-3-O-glucoside exhibited limited positional deviations; hyperoside achieved persistent accommodation following an initial adjustment, whereas isoliquiritigenin underwent a marked late rearrangement. Ensemble-based energetic analysis prioritized cyanidin-3-O-glucoside, while hyperoside and myricetin formed an energetically comparable intermediate group and isoliquiritigenin displayed the least favourable profile. Electronic-structure analysis further characterized cyanidin-3-O-glucoside as the most responsive ligand within the DFT subset. Collectively, these findings indicate that glycone-assisted polar anchoring, aromatic complementarity and restricted conformational flexibility promote persistent hSGLT2 recognition. Direct hSGLT2 inhibition and hSGLT1 counter-screening assays remain necessary to establish potency and selectivity.