Protein tyrosine phosphatase 1B (PTP-1B), has been implicated as a negative regulator of insulin receptor signaling. 1,2-Naphthoquinone skeleton was discovered as a hit toward the PTP-1B inhibitor. Here, 3D-QSAR and molecular modeling was performed on a series of 1,2-naphthoquinone derivatives. Thirty-two compounds were served to establish the model, which was validated by evaluation of an external set of 4 compounds. The best predictions were obtained with the CoMFA steric, electrostatic fields (leave-one-out q²＝0.555, no validation r²＝0.991, standard error of estimate＝0.049, F＝564.910), and with the CoMSIA combined steric, electrostatic, and lipophilic fields (leave-one-out q²＝0.558, no validation r²＝0.991, standard error of estimate＝0.050, F＝542.773). The 3D-QSAR model was then superimposed to the PTP-1B active site, giving direct contour maps of the different fields.

Key words: 1,2-naphthoquinone, 3D-QSAR, protein tyrosine phosphatase 1B