Identification of New Small-Molecule SGLT2 Inhibitors: In-Silico Approach to Therapeutics for Diabetes-Related Complications

Sodium-glucose cotransporter-2 (SGLT2) is one of the six members of the SGLT protein family that plays a key role in glucose transport in humans. SGLT2 inhibitors are drugs used to manage type 2 diabetes mellitus and offer renal and cardiovascular benefits. However, mutations in the SGLT2 protein, along with side effects of current SGLT2 inhibitors, are compelling researchers to identify new drug candidates. In this pursuit, we performed a comprehensive in silico (molecular modeling, molecular docking, drug-likeness evaluation, molecular dynamics (MD) simulation, and molecular mechanics generalized Born surface area (MM/GBSA) studies) study to identify new drug candidates. A fragment-based search strategy followed by a three-tier virtual screening led to the identification of four synthetic compounds (<b>1</b>-<b>4</b>) with docking scores (XP Gscore = - 15.8 to - 16.9 kcal/mol) better than those of the reference inhibitor dapagliflozin (Dap) (-13.9 kcal/mol). MD simulation results suggest that the compounds (<b>1</b>-<b>4</b>) stabilize the protein effectively (root-mean-square deviation, RMSD= 3.10-4.01 Å, and root-mean-square fluctuation, RMSF = 1.17-1.26 Å) compared to Dap (RMSD= 3.65 Å, RMSF = 1.18 Å). Besides, secondary structure element (SSE) analysis results suggested that the complexation of the inhibitors led to an increase in α-helices and β-strands. The MM/GBSA binding free energy values computed for the ligand-receptor complexes post-MD simulation complemented the docking results. The predicted absorption, distribution, metabolism, excretion, and toxicity (ADMET) results showed acceptable pharmacokinetic profiles. Finally, density functional theory at B3LYP/6-31G* was applied to underpin the molecular features of the compounds. Overall, this study identified new candidates against SGLT2-D201A and shed new light on the molecular and structural features of the inhibitors.