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Structure‐Based Virtual Screening Approach to the Discovery of Novel Inhibitors of Eyes Absent 2 Phosphatase with Various Metal Chelating Moieties
Author(s) -
Park Hwangseo,
Jung SukKyeong,
Yu Keum R.,
Kim Ju H.,
Kim YongSam,
Ko Jeong H.,
Park Byoung C.,
Kim Seung J.
Publication year - 2011
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/j.1747-0285.2011.01192.x
Subject(s) - virtual screening , chelation , docking (animal) , chemistry , active site , small molecule , enzyme , drug discovery , phosphatase , combinatorial chemistry , binding site , protein tyrosine phosphatase , computational biology , stereochemistry , biochemistry , biology , medicine , organic chemistry , nursing
Despite a series of persuasive experimental evidence for the involvement of eyes absent protein tyrosine phosphatases in various human cancers, no small‐molecule inhibitor has been reported so far. We have identified seven novel inhibitors of eyes absent homologue 2 (Eya2) with IC 50 values ranging from 1 to 70 μ m by the virtual screening with docking simulations and enzyme inhibition assay. Atomic charges of the active‐site Mg 2+ ion complex are calculated to enhance the accuracy of docking simulations. The newly discovered inhibitors are structurally diverse and have various chelating groups for the Mg 2+ ion. The interactions with the amino acid residues responsible for the stabilizations of the inhibitors in the active site of Eya2 are addressed in detail.