Structural basis for potent inhibition of d-amino acid oxidase by thiophene carboxylic acids.
Structural basis for potent inhibition of d-amino acid oxidase by thiophene carboxylic acids.
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DOI：
10.1016/j.ejmech.2018.09.040
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发表时间：
2018-11-05
影响因子：
6.7
通讯作者：
Tsukamoto T
中科院分区：
文献类型：
--
作者：
Kato Y;Hin N;Maita N;Thomas AG;Kurosawa S;Rojas C;Yorita K;Slusher BS;Fukui K;Tsukamoto T
一系列噻吩-2-羧酸和噻吩-3-羧酸被鉴定为一类新的DAO抑制剂。构效关系（SAR）的研究表明，小的取代基上的噻吩环的2-羧酸和3-羧酸支架耐受良好。与有效噻吩羧酸复合的人DAO的晶体结构显示，Tyr 224与抑制剂的噻吩环紧密堆叠，导致在其他DAO抑制剂中观察到的次级口袋消失。复合物的分子动力学模拟表明，Tyr 224优选的堆叠构象，无论Tyr 224是否堆叠或不在初始状态的模拟。MM/GBSA表明Tyr 244和基于噻吩的抑制剂之间存在显著的疏水相互作用。此外，活性位点紧密封闭，具有广泛的氢键网络，包括来自Tyr 224的氢键网络。在噻吩环中引入大的支链侧链显著降低了效力。这些结果与其他DAO抑制剂形成鲜明对比，其他DAO抑制剂由于Tyr 224重新定位而可以通过延伸至二级口袋的支链侧链获得效力。这些见解应该是特别重要的，在未来的努力，以优化DAO抑制剂与新的支架。
A series of thiophene-2-carboxylic acids and thiophene-3-carboxylic acids were identified as a new class of DAO inhibitors. Structure-activity relationship (SAR) studies revealed that small substituents are well-tolerated on the thiophene ring of both the 2-carboxylic acid and 3-carboxylic acid scaffolds. Crystal structures of human DAO in complex with potent thiophene carboxylic acids revealed that Tyr224 was tightly stacked with the thiophene ring of the inhibitors, resulting in the disappearance of the secondary pocket observed with other DAO inhibitors. Molecular dynamics simulations of the complex revealed that Tyr224 preferred the stacked conformation irrespective of whether Tyr224 was stacked or not in the initial state of the simulations. MM/GBSA indicated a substantial hydrophobic interaction between Tyr244 and the thiophene-based inhibitor. In addition, the active site was tightly closed with an extensive network of hydrogen bonds including those from Tyr224 in the stacked conformation. The introduction of a large branched side chain to the thiophene ring markedly decreased potency. These results are in marked contrast to other DAO inhibitors that can gain potency with a branched side chain extending to the secondary pocket due to Tyr224 repositioning. These insights should be of particular importance in future efforts to optimize DAO inhibitors with novel scaffolds.
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DOI：
10.1016/j.pbb.2010.11.009
发表时间：
2011-08
期刊：
Pharmacology, biochemistry, and behavior
影响因子：
--
作者：
Goff DC;Hill M;Barch D
通讯作者：
Barch D
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
DOI：
10.1016/j.bbrc.2007.01.181
发表时间：
2007-04-06
影响因子：
3.1
作者：
Kawazoe, Tomoya;Tsuge, Hideaki;Fukui, Kiyoshi
通讯作者：
Fukui, Kiyoshi
影响因子：
3.7
作者：
Fukushima T;Iizuka H;Yokota A;Suzuki T;Ohno C;Kono Y;Nishikiori M;Seki A;Ichiba H;Watanabe Y;Hongo S;Utsunomiya M;Nakatani M;Sadamoto K;Yoshio T
通讯作者：
Yoshio T
影响因子：
4.7
作者：
HASHIMOTO, A;NISHIKAWA, T;TAKAHASHI, K
通讯作者：
TAKAHASHI, K