Adding a Hydrogen Bond May Not Help: Naphthyridinone vs Quinoline Inhibitors of Macrophage Migration Inhibitory Factor,ACS Medicinal Chemistry Letters

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Adding a Hydrogen Bond May Not Help: Naphthyridinone vs Quinoline Inhibitors of Macrophage Migration Inhibitory Factor
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2017-11-14 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00384
Thomas K. Dawson ₁ , Pawel Dziedzic ₁ , Michael J. Robertson ₁ , José A. Cisneros ₁ , Stefan G. Krimmer ₁ , Ana S. Newton ₁ , Julian Tirado-Rives ₁ , William L. Jorgensen ₁

Affiliation

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 3a, 4a, and 4b, which show that the desired hydrogen bond is formed with O–N distances of 2.8–3.0 Å. Compound 4b is the most potent new MIF inhibitor with K_i and K_d 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.

中文翻译：

添加氢键可能无济于事：萘啶酮与巨噬细胞迁移抑制因子的喹啉抑制剂

研究了使用1，7-萘啶-8-one代替喹啉在人巨噬细胞迁移抑制因子（MIF）的活性位点上Lys32的铵基团的配位作用。模型系统的气相和水相DFT计算都表明与内酰胺羰基加成氢键的潜在好处，而FEP结果为中性。据报道，MIF与3a，4a和4b的配合物具有三种晶体结构，这表明所需的氢键是在O-N距离为2.8-3.0Å的情况下形成的。化合物4b是具有K _i和K _d的最有效的新型MIF抑制剂值为90和94 nM; 它还具有出色的水溶性，为288μg/ mL。与FEP结果一致，尽管有额外的蛋白质-配体氢键，但萘啶酮与相关喹啉的效价相似。

更新日期：2017-11-14

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