期刊
JOURNAL OF CHEMICAL INFORMATION AND MODELING
卷 55, 期 6, 页码 1120-1129出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jcim.5b00150
关键词
-
类别
资金
- CSIR network project GENESIS [BSC0121]
- CSIR
PknG is a Ser/thr protein kinase that plays a crucial role in regulatory processes within the mycobacterial cell and signaling cascade of the infected host cell. The essentiality of PknG in mycobacterial virulence by blocking phagosome lysosome fusion as well as its role in intrinsic antibiotic resistance makes it an attractive drug target. However, only very few compounds have been reported as Mycobacterium tuberculosis PknG (MtPknG) inhibitors so far. Therefore, in an effort to find potential inhibitors against MtPknG, we report here a sequential pharmacophore-based virtual screening workflow, 3-fold docking with different search algorithms, and molecular dynamic simulations for better insight into the predicted binding mode of identified hits. After detailed analysis of the results, six ligands were selected for in vitro analysis. Three of these molecules showed significant inhibitory activity against MtPknG. In addition, inhibitory studies of mycobacterial growth in infected THP-1 macrophages demonstrated considerable growth inhibition of M. bovis BCG induced through compound NRB04248 without any cytotoxic effect against host macrophages. Our results suggest that the compound NRB04248 can be explored for further design and optimization of MtPknG inhibitors.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据