6CB5

Macrophage Migration Inhibitory Factor in complex with a Pyrazole Inhibitor (8g)

Summary for 6CB5

• Entry DOI: 10.2210/pdb6cb5/pdb
• Descriptor: Macrophage migration inhibitory factor, 2-[(naphthalen-2-yl)oxy]-5-(1H-pyrazol-4-yl)benzoic acid, SULFATE ION, ... (4 entities in total)
• Functional Keywords: cd74 binding, tautomerase, inhibitor, complex, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 38248.31

Authors

Krimmer, S.G.,Robertson, M.J.,Jorgensen, W.L. (deposition date: 2018-02-02, release date: 2018-04-04, Last modification date: 2023-10-04)

Primary citation

Trivedi-Parmar, V.,Robertson, M.J.,Cisneros, J.A.,Krimmer, S.G.,Jorgensen, W.L.
Optimization of Pyrazoles as Phenol Surrogates to Yield Potent Inhibitors of Macrophage Migration Inhibitory Factor.
ChemMedChem, 13:1092-1097, 2018

PubMed Abstract: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is implicated in the regulation of inflammation, cell proliferation, and neurological disorders. MIF is also an enzyme that functions as a keto-enol tautomerase. Most potent MIF tautomerase inhibitors incorporate a phenol, which hydrogen bonds to Asn97 in the active site. Starting from a 113-μm docking hit, we report results of structure-based and computer-aided design that have provided substituted pyrazoles as phenol alternatives with potencies of 60-70 nm. Crystal structures of complexes of MIF with the pyrazoles highlight the contributions of hydrogen bonding with Lys32 and Asn97, and aryl-aryl interactions with Tyr36, Tyr95, and Phe113 to the binding.

PubMed: 29575754
DOI: 10.1002/cmdc.201800158

Experimental method

X-RAY DIFFRACTION (1.78 Å)