| Item type |
文献 / Documents(1) |
| 公開日 |
2018-12-13 |
| アクセス権 |
|
|
アクセス権 |
open access |
| 資源タイプ |
|
|
資源タイプ識別子 |
http://purl.org/coar/resource_type/c_6501 |
|
資源タイプ |
journal article |
| 出版社版DOI |
|
|
|
関連識別子 |
https://doi.org/10.1016/j.ejmech.2018.09.040 |
|
|
関連名称 |
10.1016/j.ejmech.2018.09.040 |
| 出版タイプ |
|
|
出版タイプ |
AM |
|
出版タイプResource |
http://purl.org/coar/version/c_ab4af688f83e57aa |
| タイトル |
|
|
タイトル |
Structural basis for potent inhibition of d-amino acid oxidase by thiophene carboxylic acids |
| 著者 |
加藤, 有介
Hin, Niyada
真板, 宣夫
Thomas, Ajit G.
クロサワ, スミレ
Rojas, Camilo
頼田, 和子
Slusher, Barbara S.
福井, 清
ツカモト, タカシ
|
| 抄録 |
|
|
内容記述 |
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. |
| キーワード |
|
|
主題 |
Flavoenzyme |
| キーワード |
|
|
主題 |
Schizophrenia |
| キーワード |
|
|
主題 |
Drug discovery |
| キーワード |
|
|
主題 |
X-ray crystallography |
| キーワード |
|
|
主題 |
Molecular dynamics |
| 書誌情報 |
en : European Journal of Medicinal Chemistry
巻 159,
p. 23-34,
発行日 2018-09-18
|
| 収録物ID |
|
|
収録物識別子タイプ |
ISSN |
|
収録物識別子 |
02235234 |
| 収録物ID |
|
|
収録物識別子タイプ |
NCID |
|
収録物識別子 |
AA00639621 |
| 収録物ID |
|
|
収録物識別子タイプ |
NCID |
|
収録物識別子 |
AA11526886 |
| 出版者 |
|
|
出版者 |
Elsevier |
| 権利情報 |
|
|
権利情報 |
© 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
| EID |
|
|
識別子 |
346353 |
| 言語 |
|
|
言語 |
eng |
ejmech_159_23.pdf (5.45 MB)
