Register      Login
Australian Journal of Chemistry Australian Journal of Chemistry Society
An international journal for chemical science
Shopping Cart: ( empty )
You are here: Home > Journals > CH > CH12051
RESEARCH FRONT
Contents Vol 65(9)

Structural Insights into the Active Site of Human Sodium Dependent Glucose Co-Transporter 2: Homology Modelling, Molecular Docking, and 3D-QSAR Studies

Srinivas Nakka A and Lalitha Guruprasad A B
+ Author Affiliations
- Author Affiliations

A School of Chemistry, University of Hyderabad, Hyderabad 500046, India.

B Corresponding author. Email: lgpsc@uohyd.ernet.in

Australian Journal of Chemistry 65(9) 1314-1324 https://doi.org/10.1071/CH12051
Submitted: 29 January 2012  Accepted: 27 April 2012   Published: 5 June 2012

Abstract

Human sodium dependent glucose co-transporter 2 (hSGLT2) is a target for diabetes mellitus type 2 (T2DM). The 3D (three dimensional) homology model of hSGLT2 comprising 14 transmembrane helical domains was constructed and molecular docking of the inhibitors, C-aryl glucoside analogues, into the active site was studied. The 3D-QSAR (quantitative structure activity relationship) analysis was carried out on 43 C-aryl glucoside analogues as a training set. The molecular field analysis (MFA) with G/PLS (genetic partial least-squares) method was used to generate statistically significant 3D-QSAR (r2 = 0.857) based on a molecular field generated using electrostatic and steric probes. The QSAR model was validated using leave-one-out cross-validation, bootstrapping, and randomisation methods, and finally with an external test set comprising 10 inhibitors. The molecular docking studies provide structural insights into the active site and key interactions involved in the binding of inhibitors to hSGLT2 and these results corroborate with the 3D-QSAR analysis that provide the active conformation of inhibitors and the nature of interactive fields important for activity.


References

[1]  A. Dwarakanathan, J. Insur. Med. 2006, 38, 20.

[2]  American Diabetes Association Diabetes Care 2008, 31, S55.
         | Crossref | GoogleScholarGoogle Scholar |

[3]  (a) D. Porte, Diabetes Metab. Res. Rev. 2001, 17, 181.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXlslOhuro%3D&md5=8e8ecdd8d95bfd34ce8a200d455e2cf8CAS |
      (b) R. Kikkawa, Br. J. Nutr. 2000, 84, 183.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) S. V. Edelman, Med. Clin. North Am. 1998, 82, 665.
         | Crossref | GoogleScholarGoogle Scholar |

[4]  E. C. Chao, R. R. Henry, Nat. Rev. Drug Discov. 2010, 9, 551.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXmsF2itLc%3D&md5=23b1c9929852b46563056d08e6dafb1fCAS |

[5]  O. Marsenic, Am. J. Kidney Dis. 2009, 53, 875.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXlvFOjs7o%3D&md5=13377be033d36835770a247b45d19d94CAS |

[6]  B. Mackenzie, D. D. Loo, M. Panayotova-Heiermann, E. M. Wright, J. Biol. Chem. 1996, 20, 32678.
         | Crossref | GoogleScholarGoogle Scholar |

[7]  E. M. Wright, E. Turk, Pflugers Arch. 2004, 447, 813.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXhtVygt7w%3D&md5=97886d5ea73b0e508b354d5bf3a46144CAS |

[8]  O. W. Moe, C. A. Berry, F. C. Rector, Jr, Renal Transport of Glucose, Amino Acids, Sodium, Chloride and Water, in Brenner and Rector’s the Kidney 1996, 5th ed., pp. 375–415 (Ed. B. M. Brenner) (W. B. Saunders: Philadelphia, PA).

[9]  W. S. Lee, Y. Kanai, R. G. Wells, M. A. Hediger, J. Biol. Chem. 1994, 269, 12032.
         | 1:CAS:528:DyaK2cXksFals7o%3D&md5=ba631b7f3361a6aaee5b0d33032e219cCAS |

[10]  (a) D. M. Kendall, M. C. Riddle, J. Rosenstock, D. Zhuang, D. D. Kim, M. S. Fineman, A. D. Baron, Diabetes Care 2005, 28, 1083.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXksF2hu7s%3D&md5=731150d5239b130f7ce798099fa91850CAS |
      (b) B. Zinman, B. J. Hoogwerf, S. D. Garcia, D. R. Milton, J. M. Giaconia, D. D. Kim, M. E. Trautmann, R. G. Brodows, Ann. Intern. Med. 2007, 146, 477.

[11]  A. Sali, T. L. Blundell, J. Mol. Biol. 1993, 234, 779.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2cXnt1ylug%3D%3D&md5=b8865bb32f397b171e2bb353ecff120aCAS |

[12]  Insight II User Guide 2000 (Biosym/MSI: San Diego, CA).

[13]  G. Wu, D. H. Robertson, C. L. Brooks, M. Vieth, J. Comput. Chem. 2003, 24, 1549.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXntFent70%3D&md5=169711b8285c1367f6f76ec33864b38aCAS |

[14]  Cerius2 Molecular Modelling Program Package, version 4.9.

[15]  D. Rogers, A. J. Hopfinger, J. Chem. Inf. Comput. Sci. 1994, 34, 854.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2cXkslejt7s%3D&md5=9e9d41c8dae77e8e1d996f79472e1d87CAS |

[16]  S. Faham, A. Watanabe, G. M. Besserer, D. Cascio, A. Specht, B. A. Hirayama, E. M. Wright, J. Abramson, Science 2008, 321, 810.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXptlyhsLs%3D&md5=110061ec486c3eece5bbeca4872774deCAS |

[17]  G. N. Ramachandran, V. Sasisekharan, Adv. Protein Chem. 1968, 23, 283.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaE3cXhtFOmsL8%3D&md5=3ab1cfb6d3a72e7a98768cfdd1f5deb6CAS |

[18]  D. M. Hawkins, S. C. Basak, D. Mills, J. Chem. Inf. Comput. Sci. 2003, 43, 579.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXlsFartA%3D%3D&md5=05e6e248baeb3b46a462505242ea6d53CAS |

[19]  P. P. Roy, K. Roy, QSAR Comb. Sci. 2008, 27, 302.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXlt1Kqsbg%3D&md5=414d8a04fb81375b725fe237b964ca39CAS |

[20]  J. Shi, T. L. Blundell, K. Mizuguchi, J. Mol. Biol. 2001, 310, 243.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXksFSrs70%3D&md5=1638ef151bf01f16972bb9acd8bdeb8dCAS |

[21]  R. A. Laskowski, M. W. MacArthur, D. S. Moss, J. M. Thornton, J. Appl. Cryst. 1993, 26, 283.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK3sXit12lurY%3D&md5=fe6462c2ecb03b6ae46540ea2e22dda1CAS |

[22]  (a) J. Lee, J. Y. Kim, J. Choi, S. H. Lee, J. Kim, J. Lee, Bioorg. Med. Chem. Lett. 2010, 20, 7046.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXhtl2gtLnL&md5=47b12f97ed2e4585501f18fb8a4430a8CAS |
      (b) M. J. Kim, J. Lee, S. Y. Kang, S. H. Lee, E. J. Son, M. E. Jung, S. H. Lee, K. S. Song, M. W. Lee, H. K. Han, J. Kim, J. Lee, Bioorg. Med. Chem. Lett. 2010, 20, 3420.
         | Crossref | GoogleScholarGoogle Scholar |

[23]  A. K. Rappe, C. J. Casewit, K. S. Colwell, W. A. Goddard, W. M. Skiff, J. Am. Chem. Soc. 1992, 114, 10024.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK38Xmtl2qur8%3D&md5=6b78574ad01ca06fb5e2bd92ca4521d2CAS |

[24]  A. Hirashima, T. Eiraku, E. Kuwano, M. Eto, Internet Electron. J. Mol. Des. 2003, 2, 511.
         | 1:CAS:528:DC%2BD2cXhtlalsrs%3D&md5=ec7a120b1c1f5e713f81521e1b564f44CAS |

[25]  Y. Fan, L. M. Shi, K. W. Kohn, Y. Pommier, J. N. Weinstein, J. Med. Chem. 2001, 44, 3254.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXmtlKntbk%3D&md5=166d5b6abf5adf5eb12c57dd23f4e888CAS |

[26]  R. Mannhold, P. Kroogsgrad- Larsen, QSAR Hansch Analysis and Related Approaches, in Methods and Principles in Medicinal Chemistry 1993, Volume 1, pp. 91–105 (Ed. H. Timmerman) (VCH Verlagsgesellschaft mbH: Weinheim).