化学信息学
泛素连接酶
虚拟筛选
药物发现
对接(动物)
泛素
计算生物学
配体(生物化学)
泛素蛋白连接酶类
化学
生物
生物信息学
生物化学
医学
受体
基因
护理部
作者
Serah Kimani,Julie Owen,Stuart R. Green,Fengling Li,Yanjun Li,Aiping Dong,Peter J. Brown,Suzanne Ackloo,David Kuter,Cindy Yang,Miranda MacAskill,Stephen S. MacKinnon,C.H. Arrowsmith,Matthieu Schapira,Vijay Shahani,Levon Halabelian
标识
DOI:10.1021/acs.jcim.3c00082
摘要
DCAF1 functions as a substrate recruitment subunit for the RING-type CRL4DCAF1 and the HECT family EDVPDCAF1 E3 ubiquitin ligases. The WDR domain of DCAF1 serves as a binding platform for substrate proteins and is also targeted by HIV and SIV lentiviral adaptors to induce the ubiquitination and proteasomal degradation of antiviral host factors. It is therefore attractive both as a potential therapeutic target for the development of chemical inhibitors and as an E3 ligase that could be recruited by novel PROTACs for targeted protein degradation. In this study, we used a proteome-scale drug–target interaction prediction model, MatchMaker, combined with cheminformatics filtering and docking to identify ligands for the DCAF1 WDR domain. Biophysical screening and X-ray crystallographic studies of the predicted binders confirmed a selective ligand occupying the central cavity of the WDR domain. This study shows that artificial intelligence-enabled virtual screening methods can successfully be applied in the absence of previously known ligands.
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