Discovery of Ubiquitin-Specific Protease 7 (USP7) Inhibitors with Novel Scaffold Structures by Virtual Screening, Molecular Dynamics Simulation, and Biological Evaluation
Discovery of Ubiquitin-Specific Protease 7 (USP7) Inhibitors with Novel Scaffold Structures by Virtual Screening, Molecular Dynamics Simulation, and Biological Evaluation
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通过虚拟筛选、分子动力学模拟和生物学评价发现具有新型支架结构的泛素特异性蛋白酶 7 (USP7) 抑制剂
DOI：
10.1021/acs.jcim.0c00154
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发表时间：
2020-06-22
影响因子：
5.6
通讯作者：
Yuan, Haoliang
中科院分区：
文献类型：
--
作者：
Liu, Shengjie;Zhou, Xinyu;Yuan, Haoliang
USP7被认为是治疗癌症的潜在靶点。本研究采用虚拟筛选、分子动力学(MD)模拟和生物学评价等方法，以催化活性中心为靶点，寻找新型USP7抑制剂。其中，具有新型骨架结构的化合物12具有一定的USP7抑制活性(Ub-AMC法IC50为18.40±1.75μM，Ub-Rho法IC50为7.75μM)。该HIT化合物与USP7CD的Kd值为4.46±0.86μM。体外初步研究表明，USP7CD对人前列腺癌LNCaP细胞具有抗增殖活性，IC50值为15.43±3.49μM。MD模拟揭示了USP7CD与配体(包括参考化合物ALM4和化合物12)之间蛋白质-配体相互作用的详细差异，为提高12的生物活性提供了一些重要信息。
USP7 has been regarded as a potential therapeutic target for cancer. In this study, virtual screening, molecular dynamics (MD) simulation and biological evaluation have been applied for the discovery of novel USP7 inhibitors targeting the catalytic active site. Among the obtained compounds, compound 12 with a novel scaffold structure exhibited certain USP7 inhibitory activity (Ub-AMC assay IC50: 18.40 ± 1.75 μM, Ub-Rho assay IC50 = 7.75 μM). The binding affinity between USP7CD (USP7 catalytic domain) and this hit compound was confirmed with a KD value of 4.46 ± 0.86 μM. Preliminary in vitro studies disclosed its anti-proliferative activity on human prostate cancer cell line LNCaP with an IC50 value of 15.43 ± 3.49 μM. MD simulation revealed the detailed differences of protein-ligand interactions between USP7CD and the ligands, including the reference compound ALM4 and compound 12, providing some important information for improving the bioactivity of 12. This hit compound will serve as a promising start point for facilitating the further discovery of novel USP7 inhibitors.