4WR8

Macrophage Migration Inhibitory Factor in complex with a biaryltriazole inhibitor (3b-180)

4WR8 の概要

• エントリーDOI: 10.2210/pdb4wr8/pdb
• 関連するPDBエントリー: 4WRB
• 分子名称: Macrophage migration inhibitory factor, SULFATE ION, 4-[4-(quinolin-2-yl)-1H-1,2,3-triazol-1-yl]phenol, ... (5 entities in total)
• 機能のキーワード: cd74 binding, tautomerase, inhibitor, complex, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 18
• 化学式量合計: 229281.14

構造登録者

Robertson, M.J.,Baxter, R.H.G.,Jorgensen, W.L. (登録日: 2014-10-23, 公開日: 2015-03-11, 最終更新日: 2023-12-27)

主引用文献

Dziedzic, P.,Cisneros, J.A.,Robertson, M.J.,Hare, A.A.,Danford, N.E.,Baxter, R.H.,Jorgensen, W.L.
Design, synthesis, and protein crystallography of biaryltriazoles as potent tautomerase inhibitors of macrophage migration inhibitory factor.
J.Am.Chem.Soc., 137:2996-3003, 2015

PubMed Abstract: Optimization is reported for biaryltriazoles as inhibitors of the tautomerase activity of human macrophage migration inhibitory factor (MIF), a proinflammatory cytokine associated with numerous inflammatory diseases and cancer. A combined approach was taken featuring organic synthesis, enzymatic assaying, crystallography, and modeling including free-energy perturbation (FEP) calculations. X-ray crystal structures for 3a and 3b bound to MIF are reported and provided a basis for the modeling efforts. The accommodation of the inhibitors in the binding site is striking with multiple hydrogen bonds and aryl-aryl interactions. Additional modeling encouraged pursuit of 5-phenoxyquinolinyl analogues, which led to the very potent compound 3s. Activity was further enhanced by addition of a fluorine atom adjacent to the phenolic hydroxyl group as in 3w, 3z, 3aa, and 3bb to strengthen a key hydrogen bond. It is also shown that physical properties of the compounds can be modulated by variation of solvent-exposed substituents. Several of the compounds are likely the most potent known MIF tautomerase inhibitors; the most active ones are more than 1000-fold more active than the well-studied (R)-ISO-1 and more than 200-fold more active than the chromen-4-one Orita-13.

PubMed: 25697265
DOI: 10.1021/ja512112j

実験手法

X-RAY DIFFRACTION (2.6 Å)