Department of Chemistry, Yale University, New Haven, CT, 06520-8107, USA.
ChemMedChem. 2018 Jun 6;13(11):1092-1097. doi: 10.1002/cmdc.201800158. Epub 2018 Apr 23.
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.
巨噬细胞移动抑制因子（MIF）是一种前炎性细胞因子，参与炎症、细胞增殖和神经紊乱的调控。MIF 也是一种作为酮-烯醇互变异构酶发挥作用的酶。最强的 MIF 互变异构酶抑制剂包含一个酚，它与活性部位的 Asn97 氢键结合。从一个 113μm 的对接命中，我们报告了基于结构和计算机辅助设计的结果，这些结果提供了取代的吡唑作为酚的替代物，其效力为 60-70nm。MIF 与吡唑的复合物的晶体结构突出了与 Lys32 和 Asn97 的氢键以及与 Tyr36、Tyr95 和 Phe113 的芳基-芳基相互作用对结合的贡献。
