Structural insights into the active site of human sodium dependent glucose Co-transporter 2: Homology modelling, molecular docking, and 3D-QSAR studies

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 (r 2≤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. © 2012 CSIRO.