title: Structure-based virtual screening approach to the discovery of novel inhibitors of eyes absent 2 phosphatase with various metal chelating moieties.
abstract: 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 μm 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.
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University, 98 Kunja-Dong, Kwangjin-Ku, Seoul 143-747, Korea. hspark@sejong.ac.kr
authors.forename: Hwangseo
authors.initials: H
authors.lastname: Park
authors.forename: Suk-Kyeong
authors.initials: SK
authors.lastname: Jung
authors.forename: Keum R
authors.initials: KR
authors.lastname: Yu
authors.forename: Ju H
authors.initials: JH
authors.lastname: Kim
authors.forename: Yong-Sam
authors.initials: YS
authors.lastname: Kim
authors.forename: Jeong H
authors.initials: JH
authors.lastname: Ko
authors.forename: Byoung C
authors.initials: BC
authors.lastname: Park
authors.forename: Seung J
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D020134:Catalytic Domain; D002614:Chelating Agents / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D002614:Chelating Agents; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C106938:EYA2 protein, human; D017027:Protein Tyrosine Phosphatases