6B1C

Macrophage Migration Inhibitory Factor in complex with a Naphthyridinone Inhibitor (4a)

6B1C の概要

• エントリーDOI: 10.2210/pdb6b1c/pdb
• 関連するPDBエントリー: 6B1K 6B2C
• 分子名称: Macrophage migration inhibitory factor, SULFATE ION, 2-[1-(3-fluoro-4-hydroxyphenyl)-1H-1,2,3-triazol-4-yl]-7-methyl-1,7-naphthyridin-8(7H)-one, ... (4 entities in total)
• 機能のキーワード: cd74 binding, tautomerase, inhibitor, complex, isomerase-isomerase inhibitor complex, isomerase, isomerase/isomerase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 38124.04

構造登録者

Krimmer, S.G.,Robertson, M.J.,Jorgensen, W.L. (登録日: 2017-09-18, 公開日: 2018-01-03, 最終更新日: 2023-10-04)

主引用文献

Dawson, T.K.,Dziedzic, P.,Robertson, M.J.,Cisneros, J.A.,Krimmer, S.G.,Newton, A.S.,Tirado-Rives, J.,Jorgensen, W.L.
Adding a Hydrogen Bond May Not Help: Naphthyridinone vs Quinoline Inhibitors of Macrophage Migration Inhibitory Factor.
ACS Med Chem Lett, 8:1287-1291, 2017

PubMed Abstract: Coordination of the ammonium group of Lys32 in the active site of human macrophage migration inhibitory factor (MIF) using a 1,7-naphthyridin-8-one instead of a quinoline is investigated. Both gas- and aqueous-phase DFT calculations for model systems indicate potential benefits for the added hydrogen bond with the lactam carbonyl group, while FEP results are neutral. Three crystal structures are reported for complexes of MIF with , , and , which show that the desired hydrogen bond is formed with O-N distances of 2.8-3.0 Å. Compound is the most potent new MIF inhibitor with and values of 90 and 94 nM; it also has excellent aqueous solubility, 288 μg/mL. Consistent with the FEP results, the naphthyridinones are found to have similar potency as related quinolines in spite of the additional protein-ligand hydrogen bond.

PubMed: 29259749
DOI: 10.1021/acsmedchemlett.7b00384

実験手法

X-RAY DIFFRACTION (2.163 Å)