ID 112839
Author
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
Keywords
Flavoenzyme
Schizophrenia
Drug discovery
X-ray crystallography
Molecular dynamics
Content Type
Journal Article
Description
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.
Journal Title
European Journal of Medicinal Chemistry
ISSN
02235234
NCID
AA00639621
AA11526886
Publisher
Elsevier
Volume
159
Start Page
23
End Page
34
Published Date
2018-09-18
Remark
論文本文は2020-09-18以降公開予定
Rights
© 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
DOI (Published Version)
URL ( Publisher's Version )
language
eng
TextVersion
その他
departments
Institute of Advanced Medical Sciences