ID 112839
著者
Hin, Niyada Johns Hopkins University
Thomas, Ajit G. Johns Hopkins University
Kurosawa, Sumire Tokushima University
Rojas, Camilo Johns Hopkins University
Slusher, Barbara S. Johns Hopkins University
Tsukamoto, Takashi Johns Hopkins University
キーワード
Flavoenzyme
Schizophrenia
Drug discovery
X-ray crystallography
Molecular dynamics
資料タイプ
学術雑誌論文
抄録
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.
掲載誌名
European Journal of Medicinal Chemistry
ISSN
02235234
cat書誌ID
AA00639621
AA11526886
出版者
Elsevier
159
開始ページ
23
終了ページ
34
発行日
2018-09-18
備考
論文本文は2020-09-18以降公開予定
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/)
EDB ID
346353
出版社版DOI
出版社版URL
言語
eng
著者版フラグ
その他
部局
先端酵素学研究所