The Structural Basis for Nonsteroidal Anti-Inflammatory Drug Inhibition of Human Dihydrofolate Reductase.
The Structural Basis for Nonsteroidal Anti-Inflammatory Drug Inhibition of Human Dihydrofolate Reductase.
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DOI：
10.1021/acs.jmedchem.0c00546
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发表时间：
2020-08-13
影响因子：
7.3
通讯作者：
London RE
中科院分区：
文献类型：
--
作者：
Duff MR Jr;Gabel SA;Pedersen LC;DeRose EF;Krahn JM;Howell EE;London RE
虽然NSAID主要靶向环氧合酶，但也有报道称含有羧酸基团的NSAID子集可竞争性抑制二氢叶酸还原酶（DHFR）。在这项研究中，我们已经确定了NSAID与人DHFR的相互作用的动力学，NMR和X-射线晶体学方法的基础上。NSAID靶向与叶酸的对氨基苯甲酰基-L-谷氨酸（pABG）部分相互作用的叶酸结合位点区域，并与靶向相邻蝶啶识别亚位点的配体协同抑制。含有苯甲酸酯或水杨酸酯基团的非甾体抗炎药被认为具有最高的功效。在这些测试中，二氟尼柳，一种水杨酸衍生物，以前没有被确定为具有抗叶酸活性，被发现具有34 μM的Ki，远低于在典型剂量水平下达到的血浆二氟尼柳峰值水平。这些药物通过多种途径干扰炎症过程的潜力引入了进一步优化以设计双靶向类似物的可能性。
Although NSAIDs target primarily cyclooxygenase enzymes, a subset of NSAIDs containing carboxylate groups also has been reported to competitively inhibit dihydrofolate reductase (DHFR). In this study, we have characterized NSAID interactions with human DHFR based on kinetic, NMR, and X-ray crystallographic methods. The NSAIDs target a region of the folate binding site that interacts with the p-aminobenzoyl-L-glutamate (pABG) moiety of folate, and inhibit cooperatively with ligands that target the adjacent pteridine-recognition subsite. NSAIDs containing benzoate or salicylate groups were identified as having the highest potency. Among those tested, diflunisal, a salicylate derivative not previously identified to have anti-folate activity, was found to have a Ki of 34 μM, well below peak plasma diflunisal levels reached at typical dosage levels. The potential of these drugs to interfere with the inflammatory process by multiple pathways introduces the possibility of further optimization to design dual targeted analogs.
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影响因子：
16.6
作者：
Lee, Ho-Jin;Wang, Nick X.;Shi, De-Li;Zheng, Jie J.
通讯作者：
Zheng, Jie J.
影响因子：
16.6
作者：
Daniels MJ;Rivers-Auty J;Schilling T;Spencer NG;Watremez W;Fasolino V;Booth SJ;White CS;Baldwin AG;Freeman S;Wong R;Latta C;Yu S;Jackson J;Fischer N;Koziel V;Pillot T;Bagnall J;Allan SM;Paszek P;Galea J;Harte MK;Eder C;Lawrence CB;Brough D
通讯作者：
Brough D
影响因子：
16.8
作者：
Bhabha, Gira;Ekiert, Damian C.;Jennewein, Madeleine;Zmasek, Christian M.;Tuttle, Lisa M.;Kroon, Gerard;Dyson, H. Jane;Godzik, Adam;Wilson, Ian A.;Wright, Peter E.
通讯作者：
Wright, Peter E.
影响因子：
27.4
作者：
Hoekstra, M;van Ede, AE;Laan, RFJM
通讯作者：
Laan, RFJM
影响因子：
2.9
作者：
BACCANARI, D;PHILLIPS, A;BURCHALL, J
通讯作者：
BURCHALL, J