Journal
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
Volume 20, Issue 8, Pages 5591-5605Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c7cp07588j
Keywords
-
Funding
- National Key R&D Program of China [2016YFA0202900]
- National Science Foundation of China [81302679]
Ask authors/readers for more resources
NIMA-related kinase 2 (Nek2) plays a significant role in cell cycle regulation, and overexpression of Nek2 has been observed in several types of carcinoma, suggesting it is a potential target for cancer therapy. In this study, we attempted to gain more insight into the binding mechanisms of a series of aminopyrazine inhibitors of Nek2 through multiple molecular modeling techniques, including molecular docking, molecular dynamics (MD) simulations and free energy calculations. The simulation results showed that the induced fit docking and ensemble docking based on multiple protein structures yield better predictions than conventional rigid receptor docking, highlighting the importance of incorporating receptor flexibility into the accurate predictions of the binding poses and binding affinities of Nek2 inhibitors. Additionally, we observed that the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculations did not show better performance than the docking scoring to rank the binding affinities of the studied inhibitors, suggesting that MM/GBSA is system-dependent and may not be the best choice for the Nek2 systems. Moreover, the detailed information on protein-ligand binding was characterized by the MM/GBSA free energy decomposition, and a number of derivatives with improved docking scores were designed. It is expected that our study can provide valuable information for the future rational design of novel and potent inhibitors of Nek2.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available