Identification of novel Trypanosoma cruzi prolyl oligopeptidase inhibitors by structure-based virtual screening
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- 作者：Hugo de Almeida ; Vincent Leroux…
- 关键词：Chagas disease ; Trypanosoma cruzi ; Prolyl oligopeptidase ; POPTc80 ; Homology modeling ; Catalytic mechanism ; Binding assays ; Structure ; based drug design ; Virtual screening ; Docking ; GOLD ; Molecular dynamics ; NAMD
- 刊名：Journal of Computer-Aided Molecular Design
- 出版年：2016
- 出版时间：December 2016
- 年：2016
- 卷：30
- 期：12
- 页码：1165-1174
- 全文大小：
- 刊物类别：Chemistry and Materials Science
- 刊物主题：Physical Chemistry; Computer Applications in Chemistry; Animal Anatomy / Morphology / Histology;
- 出版者：Springer International Publishing
- ISSN：1573-4951
- 卷排序：30
文摘
We have previously demonstrated that the secreted prolyl oligopeptidase of Trypanosoma cruzi (POPTc80) is involved in the infection process by facilitating parasite migration through the extracellular matrix. We have built a 3D structural model where POPTc80 is formed by a catalytic α/β-hydrolase domain and a β-propeller domain, and in which the substrate docks at the inter-domain interface, suggesting a “jaw opening” gating access mechanism. This preliminary model was refined by molecular dynamics simulations and next used for a virtual screening campaign, whose predictions were tested by standard binding assays. This strategy was successful as all 13 tested molecules suggested from the in silico calculations were found out to be active POPTc80 inhibitors in the micromolar range (lowest Ki at 667 nM). This work paves the way for future development of innovative drugs against Chagas disease.