Molecular Aspects of C-glycosides: Interactive Analysis of C-linked Compounds With the SGLT2 Molecular Model

Abstract

Background/aim: Interaction analysis between modeled human sodium/glucose cotransporter 2 (hSGLT2) and antidiabetic C-glycoside drugs, such as canagliflozin, dapagliflozin, ipragliflozin, empagliflozin, tofogliflozin, and luseogliflozin was performed.

Materials and methods: The hSGLT2 was modeled using the X-ray data of Vibrio parahaemolyticus SGLT2 (protein data bank ID=2XQ2) as a template. Conformational analyses of C-glycosides were performed using CAChe-Conflex. Interactive analyses between hSGLT2 and C-glycosides were performed using Molegro Virtual Docker.

Results: Canagliflozin interacted with hSGLT2 via Asn⁷⁵, Ser²⁸⁷, Lys³²¹ and Gln⁴⁵⁷ Dapagliflozin interacted with six amino acids (Arg⁴⁶, Arg⁴⁹, Ile⁷⁶, Ser⁷⁸, Met²¹⁶ and Ser³⁹³). Ipragliflozin (Ala⁶⁹, Met⁵⁹⁶ and Gln⁶⁰⁰), empagliflozin (Ser⁷⁸, Gly⁷⁹, Lys¹⁵⁴, Asp¹⁵⁸ and Ser³⁹³), tofogliflozin (Arg⁴⁹, Met²¹⁶, Ala³⁸⁹, Ser³⁹² and Ser³⁹³), and luseogliflozin (Arg⁴⁹, Ser⁷⁴, Ser⁷⁸, Gly⁷⁹, His⁸⁰, Lys¹⁵⁴, Asp¹⁵⁸ and Ser³⁹³) interacted with hSGLT2 via the amino acids described in the parentheses.

Conclusion: The binding mode of each C-glycoside drug to hSGLT2 was different, and structural features of each compound were revealed. The reactive base points of C-glycosides were the sugar moiety, with the sugar structure being important for hSGLT2 inhibitory action.

Keywords: C-glycoside; Interactive analysis; SGLT2.