In silico design of novel PIN1 inhibitors by combined of 3D-QSAR, molecular docking, molecular dynamic simulation and ADMET studies

Abstract

Due to the role of enzyme PIN1 in cancer cells, PIN1 is a promising therapeutic target. The study of the mechanism between PIN1 and thiazole inhibitors was carried out operating 3D-QSAR modeling, molecular docking, molecular dynamics simulations, in order to design high activity inhibitors. The optimal CoMSIA / SH model showed good reliability and satisfactory predictability Q2 = 0.717, R2 = 0.961, R2pred = 0.740. The predictability and precision of the generated model were assessed by the criteria of Golbraikh and Tropsha. The CoMSIA model with a contribution from steric and hydrophobic fields (CoMSIA/SH) passes all these validation protocols successfully, therefore the established model is reliable. The analysis of Contour map analysis may provide structural information to improve inhibitory function. Furthermore, molecular docking and MD simulations show stability and provide information on ligand-receptor interactions. The results served as the basis for developing new compounds and their expected inhibitory activities. The result of the physicochemical and ADMET / pharmacokinetic properties showed that these five proposed molecules are bioavailable by the oral route, high gastrointestinal absorption, good permeability and therefore do not inhibit CYP3A4 and CYP2D6. In addition, nontoxic to the Ames test and therefore these results would provide the necessary physicochemical and pharmacokinetic properties and relevant information in the analysis drug discovery