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Insight into the interaction mechanism of human SGLT2 with its inhibitors: 3D-QSAR studies, homology modeling, and molecular docking and molecular dynamics simulations

  • Lili Dong
  • Ruirui Feng
  • Jiawei Bi
  • Shengqiang Shen
  • Huizhe Lu
  • Jianjun Zhang
Original Paper
  • 361 Downloads

Abstract

Human sodium-dependent glucose co-transporter 2 (hSGLT2) is a crucial therapeutic target in the treatment of type 2 diabetes. In this study, both comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to generate three-dimensional quantitative structure–activity relationship (3D-QSAR) models. In the most accurate CoMFA-based and CoMSIA-based QSAR models, the cross-validated coefficients (r2cv) were 0.646 and 0.577, respectively, while the non-cross-validated coefficients (r2) were 0.997 and 0.991, respectively, indicating that both models were reliable. In addition, we constructed a homology model of hSGLT2 in the absence of a crystal structure. Molecular docking was performed to explore the bonding mode of inhibitors to the active site of hSGLT2. Molecular dynamics (MD) simulations and binding free energy calculations using MM-PBSA and MM-GBSA were carried out to further elucidate the interaction mechanism. With regards to binding affinity, we found that hydrogen-bond interactions of Asn51 and Glu75, located in the active site of hSGLT2, with compound 40 were critical. Hydrophobic and electrostatic interactions were shown to enhance activity, in agreement with the results obtained from docking and 3D-QSAR analysis. Our study results shed light on the interaction mode between inhibitors and hSGLT2 and may aid in the development of C-aryl glucoside SGLT2 inhibitors.

Keywords

hSGLT2 SLC5A2 Type 2 diabetes Homology modeling Molecular docking Molecular dynamics simulations 3D-QSAR 

Notes

Acknowledgements

This project was supported by the National Science Foundation for Fostering Talents in Basic Research of China (no. J1210064), the National Nature Science Foundation of China (21172257), and the National Science and Technology Pillar Program (2015BAK45B01) of China. All molecular dynamics simulation work was supported by Peking University. We would also like to thank Dr. Gu Jiangyong for helpful and productive discussions.

Supplementary material

894_2018_3582_MOESM1_ESM.docx (4.8 mb)
ESM 1 (DOCX 4867 kb)

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© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Applied Chemistry, College of ScienceChina Agricultural UniversityBeijingChina

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