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Rational Design of Coumarin Derivatives as CK2 Inhibitors by Improving the Interaction with the Hinge Region
Author(s) -
Zhang Na,
Chen Wenjuan,
Zhou Yue,
Zhao Hongtao,
Zhong Rugang
Publication year - 2016
Publication title -
molecular informatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.481
H-Index - 68
eISSN - 1868-1751
pISSN - 1868-1743
DOI - 10.1002/minf.201500091
Subject(s) - trifluoromethyl , chemistry , coumarin , hinge , in silico , stereochemistry , hydrogen bond , halogen , potency , combinatorial chemistry , in vitro , biochemistry , molecule , organic chemistry , mechanical engineering , alkyl , engineering , gene
Design of novel coumarin derivatives as CK2 inhibitors were attempted by targeting the interaction with the hinge region. A set of substituents capable of forming a hydrogen bond or halogen bond with the hinge region were screened in silico, and trifluoromethyl emerges as a promising motif by forming favorable electrostatic interaction and a presumable halogen bond with the hinge region. As proof of concept, three trifluoromethyl derivatives of coumarin were synthesized and tested in vitro. The results indicated that replacement of methyl by trifluoromethyl leads to a modest 5‐fold improvement in potency, with the most active compound being 0.4 µM. The newly designed compounds were further screened on one lung cancer cell line A549, showing low micromolar anti‐proliferative activity.