title: Virtual Screening of Some Active Human Macrophage Migration Inhibitory Factor Antagonists.
abstract: Macrophage migration inhibitory factor (MIF) is an autocrine- and paracrine-acting cytokine that is involved in several inflammatory, autoimmune, infectious, and oncogenic diseases. Clinical data have shown that inhibition of MIF, especially its tautomerase activity, with small compounds has been beneficial in some disease models. A virtual screening (VS) experiment is conducted for searching some active compounds to inhibit the tautomerase activity of MIF from the ZINC database. By using an x-ray-determined structure OXIM-11 as the query and an in-house developed two-dimensional scaffold comparing method designated as Sfilter, we have screened out some 1500 compounds for ranking by our previously published docking method ADDock. After further ranking by ADDock on 119 compounds screened, we have decided to choose 17 of them for measuring their inhibitory activity IC50 against the MIF tautomerase experimentally. The IC50's are measured using both human monocytic THP-1 cell lysate and purified recombinant human MIF protein. We have found that the IC50's measured for three searched compounds (namely, ZINC02693801, ZINC00141102, and ZINC12368346) are better than that determined for ISO-1, a known MIF tautomerase inhibitor and standard used throughout our VS experiment. Moreover, the scaffolds of most of our active compounds searched are also quite different from those searched and published by others previously.
authors.affiliation: Institute of Molecular Medicine and Department of Life Science, National Tsing Hua University, HsinChu, Taiwan, R.O.C.
authors.forename: Tsung-Lin
authors.initials: TL
authors.lastname: Tsai
authors.affiliation: Institute of Molecular Medicine and Department of Life Science, National Tsing Hua University, HsinChu, Taiwan, R.O.C. thlin@life.nthu.edu.tw.
authors.forename: Thy-Hou
authors.initials: TH
authors.lastname: Lin
mesh_terms: D020134:Catalytic Domain; D049109:Cell Proliferation; D002470:Cell Survival; D003198:Computer Simulation; D030562:Databases, Protein; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D006860:Hydrogen Bonding; D007249:Inflammation; D020128:Inhibitory Concentration 50; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D008024:Ligands; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors*; D015233:Models, Statistical; D009000:Monocytes / Q000166:cytology; D011994:Recombinant Proteins / Q000737:chemistry; D013844:Thiazoles / Q000737:chemistry; D014965:X-Rays
chemical_list: D008024:Ligands; D008263:Macrophage Migration-Inhibitory Factors; D011994:Recombinant Proteins; D013844:Thiazoles; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human
keywords: MIF tautomerase; inhibitors; virtual screening