Virtual Screening Inhibitors of Ubiquitin-specific Protease 7 combining Pharmacophore Modeling and Molecular Docking
Virtual Screening Inhibitors of Ubiquitin-specific Protease 7 combining Pharmacophore Modeling and Molecular Docking
复制标题
结合药效团建模和分子对接虚拟筛选泛素特异性蛋白酶 7 抑制剂
DOI：
10.1002/minf.202100273
复制
发表时间：
2022-02-08
影响因子：
3.6
通讯作者：
Xu, Ximing
中科院分区：
文献类型：
--
作者：
Zhang, Siyu;Wang, Yifan;Xu, Ximing
泛素特异性蛋白酶7 （USP7）是研究最广泛的去泛素酶之一。USP7在多种恶性肿瘤中表现出高表达特征，提示它是肿瘤预后的标志，也是抗肿瘤治疗的潜在药物靶点。本研究采用基于药效团模型和生物学评价的虚拟筛选方法，发现了靶向催化活性位点的新型USP7抑制剂。TS-4从215,480个小分子中筛选，发现具有USP7抑制活性。初步体外实验表明，与正常结肠癌细胞系（CCD841CoN）相比，其对人结肠癌细胞系（HCT-116和RKO）具有抗增殖活性。分子动力学（MD）模拟揭示了USP7与TS-4的结合机制。TS-4与Asp295、Phe409和Tyr514形成稳定的相互作用，这是增强其生物活性的关键。该化合物将作为一种有前景的靶向化合物，促进新型USP7抑制剂的进一步设计。
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.