期刊
CHEMMEDCHEM
卷 13, 期 11, 页码 1092-1097出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201800158
关键词
MIF inhibitors; phenol bioisosteres; protein crystallography; pyrazoles; tautomerase
资金
- US National Institutes of Health (NIH) [GM32136]
- US National Science Foundation [DGE-1122492]
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-m docking hit, we report results of structure-based and computer-aided design that have provided substituted pyrazoles as phenol alternatives with potencies of 60-70nm. 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.
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