6B1K

Macrophage Migration Inhibitory Factor in Complex with a Naphthyridinone Inhibitor (3a)

Summary for 6B1K

• Entry DOI: 10.2210/pdb6b1k/pdb
• Related: 6B1C 6B2C
• Descriptor: Macrophage migration inhibitory factor, 2-[1-(4-hydroxyphenyl)-1H-1,2,3-triazol-4-yl]-7-methyl-1,7-naphthyridin-8(7H)-one, SULFATE ION, ... (5 entities in total)
• Functional Keywords: cd74 binding, tautomerase, inhibitor, complex, isomerase-isomerase inhibitor complex, isomerase, isomerase/isomerase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 38499.47

Authors

Krimmer, S.G.,Robertson, M.J.,Jorgensen, W.L. (deposition date: 2017-09-18, release date: 2018-01-03, Last modification date: 2023-10-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.17 Å)