3D-QSAR And MD Simulations On Protein Tyrosine Phosphatase-1B Inhibitors-1, 2-Naphthoquinone Derivatives

Protein tyrosine phosphatase 1B (PTP-1B), has been implicated as negative regulator of insulin receptor signaling. 1,2-naphthoquinone skeleton was discovered as a hit toward PTP-1B inhibitor. Here, 3D-QSAR and molecular modeling were performed on a series of 1,2-naphthoquinone derivatives. 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 superimposed to the PTP-1B active site, giving direct contour maps of the different fields. The interaction pattem between PTP-1B and 1,2-naphthoquinone derivatives was then investigated by using molecular mechanics and molecular dynamics. The calculated results showed that the interaction energy,â–³E, is closely correlated with the activity of inhibitors. In addition,from the calculation of contribution of the van der Waals and electrostatic interactions toâ–³E and the analyses of the predicted structures of the complex, we found that the diference of the activities of inhibitors is attributed to the electrostatic interaction, which afford us important information for designing other 1,2-naphthoquinone derivatives. With the study of 3D-QSAR and MD simulation, a series of 1,2-naphthoquinone derivatives derived from 1,2-naphthoquinone skeleton were designed by the method of bio-isosterism. Because of the time limitation of my research, 15 novel molecules with the cyclohexyl substituent introduced to R4 were docked with PTP-1B by sybyl6.92. The docking scores showed that cyclohexyl substituent introduced to R4 is feasible, and more new substituents should be put into practice in the future.