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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
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 http://dx.doi.org/10.1071/CH12051
Submitted: 29 January 2012 Accepted: 27 April 2012 Published:
5
June
2012
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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. 
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