3D-QSAR CoMFA and CoMSIA on protein tyrosine phosphatase 1B inhibitors.

3D-QSAR and molecular modeling was performed on a series of benzofuran/benzothiophene biphenyls as protein tyrosine phosphatase 1B (PTP 1B) inhibitors with anti-hyperglycemic activity. Evaluation of 92 compounds served to establish the model, which was validated by evaluation of an external set of 26 compounds. The lowest energy conformer of most active compound (compound 54) obtained from simulated annealing was used as a template structure for the alignment. The best predictions were obtained with the CoMFA model from RMS fit and A log P as additional descriptor (r(2)(cv)=0.615, r(2)=0.842), and with the CoMSIA combined steric, electrostatic, and lipophilic fields (r(2)(cv)=0.597, r(2)=0.910). The 3D-QSAR model was then superimposed to the PTP 1B active site, giving direct contour maps of the different fields. Further comparison of the contour maps from the 3D-QSAR showed high level of compatibility with the active site of PTP 1B enzyme.