NDLI: Exploring the prominent performance of CX-4945 derivatives as protein kinase CK2 inhibitors by a combined computational study

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Wang, Xuwen Pan, Peichen Li, Youyong Li, Dan Hou, Tingjun
Description	Country affiliation: China Author Affiliation: Wang X ( Institute of Functional Nano & Soft Materials (FUNSOM) and Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, Jiangsu 215123, China.)
Abstract	Protein kinase CK2, also known as casein kinase II, is related to various cellular events and is a potential target for numerous cancers. In this study, we attempted to gain more insight into the inhibition process of CK2 by a series of CX-4945 derivatives through an integrated computational study that combines molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations. Based on the binding poses predicted by molecular docking, the MD simulations were performed to explore the dynamic binding processes for ten selected inhibitors. Then, both Molecular Mechanics/Poisson Boltzmann Surface Area (MM/PBSA) and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) techniques were employed to predict the binding affinities of the studied systems. The predicted binding energies of the selected inhibitors correlate well with their experimental activities $(r^{2}$ = 0.78). The van der Waals term is the most favorable component for the total energies. The free energy decomposition on a per residue basis reveals that the residue K68 is essential for the electrostatic interactions between CK2 and the studied inhibitors and numerous residues, including L45, V53, V66, F113, M163 and I174, play critical roles in forming van der Waals interactions with the inhibitors. Finally, a number of new derivatives were designed and the binding affinity and the predicted binding free energies of each designed molecule were obtained on the basis of molecular docking and MM/PBSA. It is expected that our research will benefit the future rational design of novel and potent inhibitors of CK2.
File Format	HTM / HTML
ISSN	1742206X
Issue Number	5
Volume Number	10
e-ISSN	17422051
Journal	Molecular BioSystems
Language	English
Publisher	Royal Society of Chemistry
Publisher Date	2014-05-01
Publisher Place	Great Britain (UK)
Access Restriction	Subscribed
Subject Keyword	Discipline Molecular Biology Discipline Biochemistry Casein Kinase Ii Antagonists & Inhibitors Molecular Dynamics Simulation Naphthyridines Pharmacology Protein Kinase Inhibitors Metabolism Drug Design Inhibitory Concentration 50 Chemistry Thermodynamics Journal Article Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Molecular Biology Biotechnology

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