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Open AccessArticle

Identification and Biological Evaluation of CK2 Allosteric Fragments through Structure-Based Virtual Screening

1
Beijing Key Laboratory of Environmental & Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China
2
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
*
Author to whom correspondence should be addressed.
Academic Editor: Brian J. Stockman
Molecules 2020, 25(1), 237; https://doi.org/10.3390/molecules25010237
Received: 29 October 2019 / Revised: 30 December 2019 / Accepted: 1 January 2020 / Published: 6 January 2020
(This article belongs to the Special Issue Fragment Based Drug Discovery)
Casein kinase II (CK2) is considered as an attractive cancer therapeutic target, and recent efforts have been made to develop its ATP-competitive inhibitors. However, achieving selectivity with respect to related kinases remains challenging due to the highly conserved ATP-binding pocket of kinases. Allosteric inhibitors, by targeting the much more diversified allosteric site relative to the highly conserved ATP-binding pocket, might be a promising strategy with the enhanced selectivity and reduced toxicity than ATP-competitive inhibitors. The previous studies have highlighted the traditional serendipitousity of discovering allosteric inhibitors owing to the complicate allosteric modulation. In this current study, we identified the novel allosteric inhibitors of CK2α by combing structure-based virtual screening and biological evaluation methods. The structure-based pharmacophore model was built based on the crystal structure of CK2α-compound 15 complex. The ChemBridge fragment library was searched by evaluating the fit values of these molecules with the optimized pharmacophore model, as well as the binding affinity of the CK2α-ligand complexes predicted by Alloscore web server. Six hits forming the holistic interaction mechanism with the αD pocket were retained after pharmacophore- and Alloscore-based screening for biological test. Compound 3 was found to be the most potent non-ATP competitive CK2α inhibitor (IC50 = 13.0 μM) with the anti-proliferative activity on A549 cancer cells (IC50 = 23.1 μM). Our results provide new clues for further development of CK2 allosteric inhibitors as anti-cancer hits. View Full-Text
Keywords: protein kinase CK2; allosteric fragments; αD pocket; virtual screening; anti-cancer hits protein kinase CK2; allosteric fragments; αD pocket; virtual screening; anti-cancer hits
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MDPI and ACS Style

Li, C.; Zhang, X.; Zhang, N.; Zhou, Y.; Sun, G.; Zhao, L.; Zhong, R. Identification and Biological Evaluation of CK2 Allosteric Fragments through Structure-Based Virtual Screening. Molecules 2020, 25, 237.

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