Design, synthesis and biological evaluation of 2-aminopyrimidinones and their 6-aza-analogs as a new class of CK2 inhibitors

Chekanov, Maksym O.; Ostrynska, Olga V.; Tarnavskyi, Sergii S.; Synyugin, Anatoliy R.; Briukhovetska, Nadiia V.; Bdzhola, Volodymyr G.; Pashenko, Alexander; Fokin, Andrey A.; Yarmoluk, S. M.

doi:10.3109/14756366.2013.837898

Cited by 3 publications

(1 citation statement)

References 30 publications

(32 reference statements)

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“…The reported ATP-noncompetitive CK2 inhibitors provide opportunities for the development of allosteric inhibitors, 18,19 which target the CK2b subunit or CK2a-CK2b interaction. As for the ATP-competitive inhibitors, several classes of them have been discovered, [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] such as tetrabromo-1H-benzotriazole (TBB), 38 coumarin derivatives, 39 emodin, 40 (5-oxo-5,6dihydroindolo[1,2-a]quinazolin-7-yl) acetic acid (IQA), 40 and pyrazolo [1,5-a] [1,3,5]triazine derivatives, 41 for representative examples. However, due to limited selectivity, potency or possible potential long-term toxicity, none of the above compounds have reached clinical trials.…”

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confidence: 99%

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

Wang

Pan

et al. 2014

Mol. BioSyst.

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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.

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