A selectivity study of sodium-dependent glucose cotransporter 2/sodium-dependent glucose cotransporter 1 inhibitors by molecular modeling

Abstract

Sodium-dependent glucose cotransporters (SGLTs) play an important role in glucose reabsorption in the kidney and have been identified as promising targets to treat diabetes. Because of the side effects like glucose and galactose malabsorption by targeting SGLT1, highly selective SGLT2 inhibitors are more promising in the treatment of diabetes. To understand the mechanism of selectivity, we conducted selectivity-based three-dimensional quantitative structure-activity relationship studies to highlight the structure requirements for highly selective SGLT2 inhibitors. The best comparative molecular field analysis and comparative molecular similarity indices analysis models showed the noncross-validated coefficient (r(2) ) of 0.967 and 0.943, respectively. The predicted correlation coefficients (r(2) pred ) of 0.974 and 0.938 validated the reliability and predictability of these models. Besides, homology models of SGLT2 and SGLT1 were also constructed to investigate the selective mechanism from structure-based perspective. Molecular dynamics simulation and binding free energy calculation were performed on the systems of a potent and selective compound interacting with SGLT2 and SGLT1 to compare the different binding modes. The simulation results showed that the stretch of the methylthio group on Met241 had an essential effect on the different binding modes between SGLT1 and SGLT2, which was consistent with the three-dimensional quantitative structure-activity relationship analysis. Hydrogen bond analysis and binding free energy calculation revealed that SGLT2 binding complex was more stable and favorable than SGLT1 complex, which was highly correlated with the experimental results. Our obtained results give useful information for the investigation of the inhibitors' selectivity between SGLT2 and SGLT1 and will help for further development of highly selective SGLT2 inhibitors.

Identification of phlorizin binding domains in sodium-glucose cotransporter family: SGLT1 as a unique model system

“…The predicted increase in hydrophobicity due to increased secondary structural contents (helices H1, 2 and 3) may promote high specificity and strong affinities of Pz or its analogs for SGLT2-PBD as compared to SGLT1. These assumptions fit quite nicely with the recently illustrated homology modeling and molecular dynamics simulation studies predicting higher stability of SGLT2 binding complexes than SGLT1 [39]. Hydrogen bond analysis and binding free energy calculation revealed the importance of structural components of SGLT2 that seem to be different in SGLT1 [39] further suggesting that increases in hydrophobicity of SGLT2-PBD, presumably via H1, H2 and H3 helical structures, might promote hydrogen bonding within the binding pocket and upon inhibitor binding.…”

Empagliflozin: a new strategy for nephroprotection in diabetes

“…С учетом локализации SGLT1 на эпителии тонкой кишки и потенциального риска развития диспепсиче-ских побочных эффектов при ингибировании SGLT1, клинически значимо соотношение селективности IC 50 SGLT1/IC 50 SGLT2 [26], максимальное из которых соот-ветствует эмпаглифлозину.…”

Discovery of Novel N-Glycoside and Non-Glycoside hSGLT2 Inhibitors for the Treatment of Type 2 Diabetes Mellitus

“…Previous studies have indicated that the hSGLT2 inhibitors fit into the binding site of hSGLT2 by interacting with several important residues, such as Asn75, His80, Glu99, Ala102, Arg267, Tyr290, Trp291, Gln457, and Pro518 [55] [56] [57] [58]. Among these important residues, Asn75, Glu99, Arg267, and Tyr290 are the most essential key residues since they form a hydrogen bonding network with hSGLT2 inhibitors [55] [56] [57] [58]. According to the above screening criteria, only 1 N-glycoside and 4 non-glycoside compounds were finally identified to be potential hSGLT2 inhibitors (Table 5).…”