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Discovery of Novel Allosteric Eg5 Inhibitors Through Structure‐Based Virtual Screening
Author(s) -
Zhang Wei,
Zhai Ling,
Lu Wenyan,
Boohaker Rebecca J.,
Padmalayam Indira,
Li Yonghe
Publication year - 2016
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12744
Subject(s) - allosteric regulation , virtual screening , computational biology , drug discovery , chemistry , biology , biochemistry , enzyme
Mitotic kinesin Eg5 is an attractive anticancer drug target. Discovery of Eg5 inhibitors has been focused on targeting the ‘ monastrol ‐binding site’. However, acquired drug resistance has been reported for such inhibitors. Therefore, identifying new Eg5 inhibitors which function through a different mechanism(s) could complement current drug candidates and improve drug efficacy. In this study, we explored a novel allosteric site of Eg5 and identified new Eg5 inhibitors through structure‐based virtual screening. Experiments with the saturation‐transfer difference NMR demonstrated that the identified Eg5 inhibitor SRI 35566 binds directly to Eg5 without involving microtubules. Moreover, SRI 35566 and its two analogs significantly induced monopolar spindle formation in colorectal cancer HCT 116 cells and suppressed cancer cell viability and colony formation. Together, our findings reveal a new allosteric regulation mechanism of Eg5 and a novel drug targeting site for cancer therapy.