Journal
MOLECULAR INFORMATICS
Volume 41, Issue 7, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/minf.202100273
Keywords
USP7 Inhibitors; Virtual screening; Molecular dynamics
Categories
Funding
- National Natural Science Foundation of China [31900910]
- Shandong Provincial Major Science and Technology Innovation Project [2020CXGC010503]
Ask authors/readers for more resources
In this study, virtual screening based on pharmacophore model was used to discover a novel USP7 inhibitor, TS-4, which exhibited inhibitory activity against USP7 and antiproliferative activity on human colon cancer cells. Molecular dynamics simulation revealed the mechanism of interaction between TS-4 and USP7.
Ubiquitin-specific protease 7 (USP7) is one of the most extensively studied deubiquitinases. USP7 exhibits a high expression signature in various malignant tumors, suggesting that it is a marker of tumor prognosis and a potential drug target for anti-tumor therapy. In this study, virtual screening based on pharmacophore model and biological evaluation have been applied for the discovery of novel USP7 inhibitors targeting the catalytic active site. The TS-4 was screened from 215,480 small molecules and was found to have USP7 inhibitory activity. Preliminary in vitro studies disclosed its antiproliferative activity on human colon cancer cell lines (HCT-116 and RKO), compared with normal colon cell line (CCD841CoN). Molecular dynamics (MD) simulation revealed the combine mechanism between USP7 with the TS-4. The TS-4 formed stable interactions with Asp295, Phe409 and Tyr514, which were critical to enhance its biological activity. This compound will serve as a promising hit compound for facilitating the further design of novel USP7 inhibitors.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available