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

Abstract

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

Keywords:

• Pin1
• pSer/Thr-Pro motifs
• molecular docking
• 3D-QSAR
• MD simulations

Acknowledgements

Lina Ding acknowledged the financial aid for International Training of High-level Talents in Henan (2017) from Henan Administration of Foreign Experts Affairs. We acknowledged the Zhengzhou University Supercomputing Center for the computational support.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by National Natural Science Foundation of China (No. 21403200 for L.-N.D.); National Key Research Program of Proteins (No. 2016YFA0501800, for H.-M.L.); Key Research Program of Henan Province (No. 161100310100, for H.-M.L.); Science and Technology Innovation Talents of Henan Provincial Education Department (19IRTSTHN001, for W. Z).