PDBsum entry 6cbh

Cytokine

PDB id: 6cbh

Contents

Protein chains

114 a.a.

Ligands

SO4 ×6

IPA ×2

GOL ×2

EWJ

Waters ×310

References listed in PDB file

Key reference

• Title: Optimization of pyrazoles as phenol surrogates to yield potent inhibitors of macrophage migration inhibitory factor.
• Authors: V.Trivedi-Parmar, M.J.Robertson, J.A.Cisneros, S.G.Krimmer, W.L.Jorgensen.
• Ref.: ChemMedChem, 2018, 13, 1092-1097.
• PubMed id: 29575754

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.