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PMID: 19090668 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Discovery of human macrophage migration inhibitory factor (MIF)-CD74 antagonists via virtual screening.

Journal of medicinal chemistry ·Vol. 52 ·No. 2 ·2009-01-22 ·Pages 416-24

Cournia Z, Leng L, Gandavadi S, Du X, Bucala R, Jorgensen WL

Abstract

Macrophage migration inhibitory factor (MIF) is a cytokine that is involved in the regulation of inflammation as well as cell proliferation and differentiation. Deactivation of MIF by antibodies or inhibition of MIF binding to its receptor, CD74, attenuates tumor growth and angiogenesis. To discover small-molecule inhibitors of MIF's biological activity, virtual screening was performed by docking 2.1 million compounds into the MIF tautomerase active site. After visual inspection of 1200 top-ranked MIF-ligand complexes, 26 possible inhibitors were selected and purchased and 23 of them were assayed. The in vitro binding assay for MIF with CD74 revealed that 11 of the compounds have inhibitory activity in the micromolar regime, including four compounds with IC(50) values below 5 microM. Inhibition of MIF tautomerase activity was also established for many of the compounds with IC(50) values as low as 0.5 microM; Michaelis-Menten analysis was performed for two cases and confirmed the competitive inhibition.

MeSH Terms
Antigens, CD/chemistry Crystallography, X-Ray Humans Hydrogen Bonding Macrophage Migration-Inhibitory Factors/antagonists & inhibitors,chemistry Molecular Structure Sialyltransferases/antagonists & inhibitors,chemistry
Chemicals
Antigens, CD Macrophage Migration-Inhibitory Factors Sialyltransferases ST6GAL1 protein, human
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Cournia Zoe
Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, USA.
Leng Lin
Gandavadi Sunilkumar
Du Xin
Bucala Richard
Jorgensen William L
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Article Info
Journal
Journal of medicinal chemistry
Abbr.
J Med Chem
ISSN
1520-4804
DOI
10.1021/jm801100v
Published
2009-01-22
Pages
416-24
Language
English
Region
United States
NLM ID
9716531
PMCID
PMC2680181
Subset
IM
Grants
NIGMS NIH HHS · R01 GM032136 · United States
NIAID NIH HHS · AI043210 · United States
NIGMS NIH HHS · GM032136 · United States
NIAMS NIH HHS · R01 AR049610 · United States
NIAMS NIH HHS · R01 AR050498-05 · United States
NIGMS NIH HHS · R01 GM032136-26 · United States
NIAMS NIH HHS · AR049610 · United States
NIAID NIH HHS · R01 AI042310 · United States
NIAMS NIH HHS · R01 AR050498 · United States
NIAID NIH HHS · R01 AI042310-11 · United States
NIAMS NIH HHS · AR050498 · United States
NIAMS NIH HHS · R01 AR049610-07 · United States
External Links
PubMed source DOI: 10.1021/jm801100v PMC Full Text View journal details
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