Abstract
Type 2 diabetes mellitus (T2DM) remains one of the leading causes of death globally. Current treatments of this disease involve using sulfonylurea, which is associated with cardiovascular risk and insulin resistance, among others. Herein, we report on the antidiabetic potential of the new sulfonylurea analogs 4a-l via an in silico-based approach. Absorption, distribution, metabolism, excretion, and toxicity (ADMET), molecular docking and dynamics, molecular mechanics generalized Born surface area (MM-GBSA), and density functional theory (DFT) were used to assess drug-likeness properties, antidiabetic activity, binding affinity, and interaction and stability of the new sulfonylurea analogs 4a-l. All compounds 4a-l showed acceptable pharmacokinetic, toxicity, and drug-like properties. Molecular docking showed that the binding affinities of the ligands 4a-o were found to be higher on SGLT2 rather than on DPP-IV inhibition, suggesting these compounds work as SGLT2 rather than as DPP-IV inhibitors. In addition, Compounds 4h, 4b, 4i, and 4j have emerged as promising inhibitors against SGLT2 with a docking score of -7.999 kcal/mol, -7.657 kcal/mol, -7.626 kcal/mol, and -7.537 kcal/mol, respectively. The root mean square deviation (RMSD) and root mean square fluctuation (RMSF) have demonstrated good structural stability throughout the simulation, ranging from 1.5 to 2.0 & Aring;. Furthermore, molecular dynamics simulations identified Asn 75 and Glu 457 as key residues consistently mediating ligand binding in both transmembrane and nontransmembrane environments. The parameters of MM-GBSA showed an acceptable free binding energy for these compounds. DFT calculations provided insights into the electronic distribution and reactivity of the lead compounds, suggesting that these compounds have the potential to be further investigated as a next treatment for T2DM. Experimental studies on the synthesis and in vitro antidiabetic evaluation of these sulfonylurea analogs 4a-l are currently underway to validate these in silico results.