Structure-based virtual screening approach to the discovery of novel inhibitors of factor-inhibiting HIF-1: Identification of new chelating groups for the active-site ferrous ion = 구조기반 FIH 억제제 virtual screening

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Title
Structure-based virtual screening approach to the discovery of novel inhibitors of factor-inhibiting HIF-1: Identification of new chelating groups for the active-site ferrous ion = 구조기반 FIH 억제제 virtual screening
Author(s)
S Ko; Myung Kyu Lee; D Shin; H Park
Bibliographic Citation
Bioorganic & Medicinal Chemistry, vol. 17, no. 22, pp. 7769-7774
Publication Year
2009
Abstract
The inhibitors of factor-inhibiting HIF-1 (FIH1) have been shown to be useful as therapeutics for the treatment of anemia. We have been able to identify eight novel FIH1 inhibitors with IC50 values ranging from 30 to 80 μM by means of the virtual screening with docking simulations under consideration of the effects of ligand solvation in the scoring function. The newly identified inhibitors are structurally diverse and have various chelating groups for the active-site ferrous ion including sulfonamide, carboxylate, N-benzo[1,2,5]oxadiazol-4-yl amide, and 2-[1,2,4]triazolo[3,4-b]][1,3,4]thiadiazol-3-yl-quinoline moieties. Each of these four structural classes has not been reported as FIH1 inhibitor, and therefore can be considered for further development by structure-activity relationship or de novo design methods. The interactions with the amino acid residues responsible for the stabilizations of the inhibitors in the active site are addressed in detail.
Keyword
AnemiaDockingFIH1InhibitorVirtual screening
ISSN
0968-0896
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.bmc.2009.09.034
Type
Article
Appears in Collections:
Division of Biomaterials Research > Bionanotechnology Research Center > 1. Journal Articles
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