Computational strategy for intrinsically disordered protein ligand design leads to the discovery of p53 transactivation domain I binding compounds that activate the p53 pathway
- 影响因子：
0.0
- DOI码：
10.1039/d0sc04670a
- 发表刊物：
Chem Sci .
- 摘要：
Intrinsically disordered proteins or intrinsically disordered regions (IDPs) have gained much attention in recent years due to their vital roles in biology and prevalence in various human diseases. Although IDPs are perceived as attractive therapeutic targets, rational drug design targeting IDPs remains challenging because of their conformational heterogeneity. Here, we propose a hierarchical computational strategy for IDP drug virtual screening (IDPDVS) and applied it in the discovery of p53 transactivation domain I (TAD1) binding compounds. IDPDVS starts from conformation sampling of the IDP target, then it combines stepwise conformational clustering with druggability evaluation to identify potential ligand binding pockets, followed by multiple docking screening runs and selection of compounds that can bind multi-conformations. p53 is an important tumor suppressor and restoration of its function provides an opportunity to inhibit cancer cell growth. TAD1 locates at the N-terminus of p53 and plays key roles in regulating p53 function. No compounds that directly bind to TAD1 have been reported due to its highly disordered structure. We successfully used IDPDVS to identify two compounds that bind p53 TAD1 and restore wild-type p53 function in cancer cells. Our study demonstrates that IDPDVS is an efficient strategy for IDP drug discovery and p53 TAD1 can be directly targeted by small molecules.
- 论文类型：
期刊论文
- 论文编号：
66
- 文献类型：
J
- 卷号：
12
- 期号：
8
- 页面范围：
3004-3016
- 是否译文：
否
- 发表时间：
2020-10-28
- 收录刊物：
SCI
- 发布期刊链接：
- 第一作者：
Hao Ruan
- 通讯作者：
Luhua Lai
- 全部作者：
Chen Yu,Xiaogang Niu,Weilin Zhang,Hanzhong Liu,Limin Chen,Ruoyao Xiong,Qi Sun,Changwen Jin,Ying Liu
