Virtual Screening Inhibitors of Ubiquitin-specific Protease 7 Combining Pharmacophore Modeling and Molecular Docking.

Siyu Zhang, Yifan Wang, Lu Liu, Guangjian Zhao, Yujie Sun, Juan Wang, Fang Liu, Peng Wang, Ximing Xu

Molecular informatics 2022 Jul

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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. © 2022 Wiley-VCH GmbH.

Citation

Siyu Zhang, Yifan Wang, Lu Liu, Guangjian Zhao, Yujie Sun, Juan Wang, Fang Liu, Peng Wang, Ximing Xu. Virtual Screening Inhibitors of Ubiquitin-specific Protease 7 Combining Pharmacophore Modeling and Molecular Docking. Molecular informatics. 2022 Jul;41(7):e2100273