Dawson Thomas K, Dziedzic Pawel, Robertson Michael J, Cisneros José A, Krimmer Stefan G, Newton Ana S, Tirado-Rives Julian, Jorgensen William L
Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States.
ACS Med Chem Lett. 2017 Nov 14;8(12):1287-1291. doi: 10.1021/acsmedchemlett.7b00384. eCollection 2017 Dec 14.
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.
研究了在人巨噬细胞迁移抑制因子（MIF）活性位点中使用1,7-萘啶-8-酮代替喹啉对Lys32铵基团的配位作用。对模型系统进行的气相和水相密度泛函理论（DFT）计算表明，与内酰胺羰基形成的额外氢键具有潜在益处，而自由能微扰（FEP）结果则呈中性。报道了MIF与[具体化合物1]、[具体化合物2]和[具体化合物3]配合物的三种晶体结构，结果表明形成了所需的氢键，O-N距离为2.8 - 3.0 Å。化合物[具体化合物3]是最有效的新型MIF抑制剂，IC50和Ki值分别为90和94 nM；它还具有出色的水溶性，为288 μg/mL。与FEP结果一致，尽管存在额外的蛋白质 - 配体氢键，但发现萘啶酮与相关喹啉具有相似的效力。
