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Development of sodium glucose co-transporter 2 (SGLT2) inhibitors with novel structure by molecular docking and dynamics simulation

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Abstract

In this study, molecular docking studies were carried out to explore the binding interactions of sodium glucose co-transporter 2 (SGLT2) with its inhibitors. A correlation between the docking scores and the experimental bioactivity was observed (R2 = 0.8368, N = 24). The new inhibitors were designed using the 3D quantitative structure activity relationship (3D-QSAR) method, and the activities were predicted by the docking method. In order to understand the structure–activity correlation of compound 1 m (the highest score of docking) and compound 1 t (the lowest score), we carried out a combined molecular dynamics simulation and MM-GBSA method. It was found that, in the system of SGLT2-1 m, the interaction between Gln271 and Val272 exhibited significant effects, which were absent in the SGLT2-1 t system. This study is expected to shed light on the mechanism of action of compound 1 m, leading to development of active drug candidates targeting SGLT2.

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References

  1. Cavaghan MK, Ehrmann DA, Polonsky KS (2000) Interactions between insulin resistance and insulin secretion in the development of glucose intolerance. J Clin Invest 106(3):329–333. https://doi.org/10.1172/JCI10761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Saltiel AR (2001) New perspectives into the molecular pathogenesis and treatment of type 2 diabetes. Cell 104(4):517–529. https://doi.org/10.1016/S0092-8674(01)00239-2

    Article  CAS  PubMed  Google Scholar 

  3. Zimmet P, Alberti KG, Shaw J (2001) Global and societal implications of the diabetes epidemic. Nature 414(6865):782–787. https://doi.org/10.1038/414782a

    Article  CAS  PubMed  Google Scholar 

  4. Bailey CJ, Aschner P, Del Prato S, LaSalle J, Ji L, Matthaei S (2013) Individualized glycaemic targets and pharmacotherapy in type 2 diabetes. Diab Vasc Dis Res 10(5):397–409

    Article  CAS  PubMed  Google Scholar 

  5. American Diabetes Association (2014) Diagnosis and classification of diabetes mellitus. Diabetes Care 37:81–90

    Article  Google Scholar 

  6. Mohler ML, He Y, Wu Z, Dong JH, Miller DD (2009) Recent and emerging anti-diabetes targets. Med Res Rev 29(1):125–195. https://doi.org/10.1002/med.20142

    Article  CAS  PubMed  Google Scholar 

  7. Hung HY, Qian K, Morris-Natschke SL, Hsu CS, Lee KH (2012) Recent discorvey of plant-derived anti-diabetic natural products. Nat Prod Rep 29(5):580–606. https://doi.org/10.1039/c2np00074a

    Article  CAS  PubMed  Google Scholar 

  8. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD (2005) Effects of exenatide (Exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 27(11):2628–2635

    Article  Google Scholar 

  9. Inzucchi SE (2002) Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 287:373–376. https://doi.org/10.1001/jama.287.3.373

    Article  Google Scholar 

  10. Isaji M (2007) Sodium-glucose cotransporter inhibitors for diabetes. Curr Opin Investig Drugs 8(4):285–292

    CAS  PubMed  Google Scholar 

  11. Neumiller JJ, White Jr JR, Campbell RK (2010) Sodium-glucose co-transport inhibitors progress and therapeutic potential in type 2 diabetes mellitus. Drugs 70(4):377–385. https://doi.org/10.2165/11318680-000000000-00000

    Article  CAS  PubMed  Google Scholar 

  12. Kinne RKH, Castaneda F (2011) SGLT inhibitors as new therapeutic tools in the treatment of diabetes. Handb Exp Pharmacol 203(203):105–126. https://doi.org/10.1007/978-3-642-17214-4_5

    Article  CAS  Google Scholar 

  13. Pajor A, Randolph KS, Smith C (2008) Inhibitor binding in the human renal low- and high-affinity Na+/glucose cotransporters. J Pharmacol Exp Ther 324(3):985–991. https://doi.org/10.1124/jpet.107.129825

    Article  CAS  PubMed  Google Scholar 

  14. Kipnes MS (2011) Sodium–glucose cotransporter 2 inhibitors in the treatment of type 2 diabetes: a review of phase II and III trials. Clin Investig 1(1):145–156. https://doi.org/10.4155/cli.10.12

    Article  CAS  Google Scholar 

  15. Kanai Y, Lee WS, You G, Brown D, Hediger MA (1994) The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J Clin Invest 93(1):397–404. https://doi.org/10.1172/JCI116972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Han S, Hagan DL, Taylor JR, Xin L, Meng W, Biller SA, Wetterau JR, Washburn WN, Whaley JM (2008) Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes 57(6):1723. https://doi.org/10.2337/db07-1472

    Article  CAS  PubMed  Google Scholar 

  17. Washburn WN (2009) Development of the renal glucose reabsorption inhibitors: a new mechanism for the pharmacotherapy of diabetes mellitus type 2. J Med Chem 40(29):1785–1794. https://doi.org/10.1021/jm8013019

    Article  CAS  Google Scholar 

  18. Gao Y, Zhao G, Liu W, Wang Y, Xu W, Wang J (2010) Thiadizole-based thiaglycosides as sodium-glucose co-transporter 2 (SGLT2) inhibitors. Chin J Chem 28(4):605–612. https://doi.org/10.1002/cjoc.201090120

    Article  CAS  Google Scholar 

  19. Li AR, Zhang J, Greenberg J, Lee T, Liu J (2011) Discovery of non-glucoside SGLT2 inhibitors. Bioorg Med Chem Lett 21(8):2472. https://doi.org/10.1016/j.bmcl.2011.02.056

    Article  CAS  PubMed  Google Scholar 

  20. Chen LH, Leung PS (2013) Inhibition of the sodium glucose co-transporter-2: its beneficial action and potential combination therapy for type 2 diabetes mellitus. Diabetes Obes Metab 15:392–402

    Article  CAS  PubMed  Google Scholar 

  21. Liu J, Lee TW (2012) Why do SGLT2 inhibitors inhibit only 30–50% of renal glucose reabsorption in humans? Diabetes 61:2199–2204. https://doi.org/10.2337/db12-0052

    Article  CAS  PubMed  Google Scholar 

  22. Tang H, Li D, Zhang J, Li Y, Wang T, Zhai S, Song Y (2017) Sodium-glucose co-transporter-2 inhibitors and risk of adverse renal outcomes among patients with type 2 diabetes: a network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab. https://doi.org/10.1111/dom.12917

    Article  CAS  PubMed  Google Scholar 

  23. Dong L, Feng R, Bi J, Shen S, Lu H, Zhang J (2018) Insight into the interaction mechanism of human SGLT2 with its inhibitors: 3D-QSAR studies, homology modeling, and molecular docking and molecular dynamics simulations. J Mol Model 24(4):86. https://doi.org/10.1007/s00894-018-3582-2

    Article  CAS  PubMed  Google Scholar 

  24. Lee J, Lee SH, Seo HJ, Son EJ, Lee SH, Jung ME, Lee M, Han HK, Kim J, Kang J, Lee J (2010) Novel C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents: 1,3,4-Thiadiazolylmethylphenyl glucoside congeners. Bioorg Med Chem 18(6):2178–2194. https://doi.org/10.1016/j.bmc.2010.01.073

    Article  CAS  PubMed  Google Scholar 

  25. Tripos Associates (2006) Sybyl 7.3. Tripos Associates, St. Louis

  26. Vettoretti G, Moroni E, Sattin S, Tao J, Agard DA, Bernardi A, Colombo G (2016) Molecular dynamics simulations reveal the mechanisms of allosteric activation of Hsp90 by designed ligands. Sci Rep 6:23830. https://doi.org/10.1038/srep23830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Case DA, Babin VB, Berryman J, Betz RM, Cai Q, Cerutti DS (2014) Amber 14. Mech Eng 126:14

    Google Scholar 

  28. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Petersson GA, Nakatsuji H, Li X, Caricato M, Marenich AV, Bloino J, Janesko BG, Gomperts R, Mennucci B, Hratchian HP, Ortiz JV, Izmaylov AF, Sonnenberg JL, Williams-Young D, Ding F, Lipparini F, Egidi F, Goings J, Peng B, Petrone A, Henderson T, Ranasinghe D, Zakrzewski VG, Gao J, Rega N, Zheng G, Liang W, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Throssell K, Montgomery Jr JA, Peralta JE, Ogliaro F, Bearpark MJ, Heyd JJ, Brothers EN, Kudin KN, Staroverov VN, Keith TA, Kobayashi R, Normand J, Raghavachari K, Rendell AP, Burant JC, Iyengar SS, Tomasi J, Cossi M, Millam JM, Klene M, Adamo C, Cammi R, Ochterski JW, Martin RL, Morokuma K, Farkas O, Foresman JB, Fox DJ (2016) Gaussian 16, revision A.03. Gaussian, Inc., Wallingford

    Google Scholar 

  29. Duan Y, Wu C, Chowdhury S, Lee MC, Xiong G, Zhang W, Yang R, Cieplak P, Luo R, Lee T (2003) A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations. J Comput Chem 24(16):1999–2012. https://doi.org/10.1002/jcc.10349

    Article  CAS  PubMed  Google Scholar 

  30. Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) Development and testing of a general amber force field. J Comput Chem 25(9):1157–1174. https://doi.org/10.1002/jcc.20035

    Article  CAS  PubMed  Google Scholar 

  31. York DM, Darden TA, Pedersen LG (1993) The effect of long-range electrostatic interactions in simulations of macromolecular crystals: a comparison of the ewald and truncated list methods. J Chem Phys 99(10):8345–8348. https://doi.org/10.1063/1.465608

    Article  CAS  Google Scholar 

  32. Ryckaert JP, Ciccotti G, Berendsen HJC (1977) Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 23(3):327–341. https://doi.org/10.1016/0021-9991(77)90098-5

    Article  CAS  Google Scholar 

  33. And DB, Case DA (2000) Generalized born models of macromolecular solvation effects. Annu Rev Phys Chem 51(1):129–152. https://doi.org/10.1146/annurev.physchem.51.1.129

    Article  Google Scholar 

  34. Jayaram B, Sprous a D, Beveridge DL (2011) Solvation free energy of biomacromolecules: parameters for a modified generalized born model consistent with the AMBER force field. J Phys Chem B 102(47):9571–9576. https://doi.org/10.1021/jp982007x

    Article  Google Scholar 

  35. Wang J, Hou T, Xu X (2006) Recent advances in free energy calculations with a combination of molecular mechanics and continuum models. Curr Comput Aided Drug Des 2(3):287–306. https://doi.org/10.2174/157340906778226454

    Article  CAS  Google Scholar 

  36. Greenidge PA, Kramer C, Mozziconacci JC, Wolf RM (2013) MM/GBSA binding energy prediction on the PDB bind data set: successes, failures, and directions for further improvement. J Chem Inf Model 53(1):201–209. https://doi.org/10.1021/ci300425v

    Article  CAS  PubMed  Google Scholar 

  37. Liu W, Wang H, Meng F (2015) In silico modeling of aspalathin and nothofagin against SGLT2. J Theor Comput Chem 14(08):1550056. https://doi.org/10.1142/S021963361550056X

    Article  CAS  Google Scholar 

  38. Nakka S, Guruprasad L (2012) Structural insights into the active site of human sodium dependent glucose co-transporter 2: homology modelling, molecular docking, and 3D-QSAR studies. Aust J Chem 65(9):1314–1324. https://doi.org/10.1071/CH12051

    Article  CAS  Google Scholar 

  39. Sharp KA (1994) Electrostatic interactions in macromolecules. Curr Opin Struct Biol 4(2):234–239. https://doi.org/10.1016/S0959-440X(94)90314-X

    Article  CAS  Google Scholar 

  40. Meyer EA, Castellano RK, Diederich F (2003) Interactions with aromatic rings in chemical and biological recognition. Angew Chem Int Ed 42:1210–1250. https://doi.org/10.1002/anie.200390319

    Article  CAS  Google Scholar 

  41. Lu Y, Shi T, Wang Y, Yang H, Yan X, Luo X, Jiang H, Zhu W (2009) Halogen bonding-a novel interaction for rational drug design? J Med Chem 52(9):2854–2862. https://doi.org/10.1021/jm9000133

    Article  CAS  PubMed  Google Scholar 

  42. Lyne PD, Lamb ML, Saeh JC (2006) Accurate prediction of the relative potencies of members of a series of kinase inhibitors using molecular docking and mm-gbsa scoring. J Med Chem 49(16):4805–4808. https://doi.org/10.1021/jm060522a

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We gratefully acknowledge financial support by the National Nature Science Foundation of China (21172230) and the National Nature Science Foundation of China (21873115).

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Authors and Affiliations

  1. Department of Applied Chemistry, College of Science, China Agricultural University, Beijing, 100193, China

    Ruirui Feng, Lili Dong, Leng Wang, Yefei Xu, Huizhe Lu & Jianjun Zhang

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  1. Ruirui Feng
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Correspondence to Huizhe Lu or Jianjun Zhang.

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Feng, R., Dong, L., Wang, L. et al. Development of sodium glucose co-transporter 2 (SGLT2) inhibitors with novel structure by molecular docking and dynamics simulation. J Mol Model 25, 175 (2019). https://doi.org/10.1007/s00894-019-4067-7

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