Molecular docking, 3D-QASR and molecular dynamics simulations of thiazoles Pin1 inhibitors.

Pin1 (protein interacting with never-in-mitosis akinase-1) is a member of the PPIase (peptidylprolyl cis-trans isomerase) family. It can interact with a variety of carcinogenic or tumor suppressive phosphorylated proteins. The interaction results in the conformational changes of target proteins, and ultimately regulates the activity of these proteins. These activity changes play a key role in tumorigenesis. Pin1 is an attractive target for cancer therapy due to its over-expression and/or activation in various types of cancer and the disorder of Proline directed phosphorylation. In this study, molecular docking, three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular dynamics (MD) simulations were performed to investigate the structure-activity relationship and binding mechanism of 45 thiazole-class Pin1 inhibitors. Molecular docking studies predict the binding mode and the interactions between the ligand and the receptor protein. The results of the 3 D-QSAR model show that electrostatic field, hydrophobic field and hydrogen bond play important roles in the binding process of inhibitors to protein. Molecular dynamics simulation results reveal that the complex of the ligand and the receptor protein are stable at 300 K. The binding free energy calculation and energy decomposition results show that His59, Cys113, Ser114, Ser115, Leu122, Met130, Gln131, Phe134, Ser154 and His157 may be the key to the inhibitor binding to Pin1 protein. This study provides an important theoretical basis for further development of the new Pin1 inhibitor design. These results can provide more useful information for our further drug design. Communicated by Ramaswamy H. Sarma.

Investigating the binding mechanism of piperidinyl ureas inhibitors based on the UBC12-DCN1 interaction by 3D-QSAR, molecular docking and molecular dynamics simulations.

Neddylation regulates a variety of biological processes by modulating Cullin-RING E3 ubiquitin ligases (CRLs) which is considered to be an important target for human diseases. The activation of CRLs required Cullins Neddylation, which regulated by the interaction of UBC12-DCN1 complex. Here, to investigate the structure-activity relationship and binding mechanism of 41 piperidinyl ureas inhibitors based on the UBC12-DCN1 protein-protein interaction, we carried out molecular modeling studies using three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations.Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to generate 3D-QSAR models. The results show that the best CoMFA model has q2=0.736, r2ncv=0.978, r2pred=0.78 (CoMFA), and the best CoMSIA model has q2=0.761, r2ncv=0.987, r2pred=0.86. The electrostatic, hydrophobic and H-bond donor fields play important roles in the models. Molecular docking studies predict the binding mode and the interactions between the ligand and the receptor protein. Molecular dynamics simulations results reveal that the complex of the ligand and the receptor protein are stable at 300 K. The results of MM-GBSA indicated the residues of Ile1083, Ile1086, Ala1098, Val1102, Ile1105, Gln1114, Phe1164 and Leu1184 might be the key residues during the process of inhibitors bound to DCN1. This study could provide an important theoretical basis for further developing novel inhibitors design based on UBC12-DCN1 protein-protein interaction. All the results can provide us more useful information for our further drug design. Communicated by Ramaswamy H. Sarma.