Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, PR China; College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, PR China.
College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, PR China.
Comput Biol Med. 2024 May;174:108397. doi: 10.1016/j.compbiomed.2024.108397. Epub 2024 Apr 2.
The equilibrium of cellular protein levels is pivotal for maintaining normal physiological functions. USP5 belongs to the deubiquitination enzyme (DUBs) family, controlling protein degradation and preserving cellular protein homeostasis. Aberrant expression of USP5 is implicated in a variety of diseases, including cancer, neurodegenerative diseases, and inflammatory diseases. In this paper, a multi-level virtual screening (VS) approach was employed to target the zinc finger ubiquitin-binding domain (ZnF-UBD) of USP5, leading to the identification of a highly promising candidate compound 0456-0049. Molecular dynamics (MD) simulations were then employed to assess the stability of complex binding and predict hotspot residues in interactions. The results indicated that the candidate stably binds to the ZnF-UBD of USP5 through crucial interactions with residues ARG221, TRP209, GLY220, ASN207, TYR261, TYR259, and MET266. Binding free energy calculations, along with umbrella sampling (US) simulations, underscored a superior binding affinity of the candidate relative to known inhibitors. Moreover, US simulations revealed conformational changes of USP5 during ligand dissociation. These insights provide a valuable foundation for the development of novel inhibitors targeting USP5.
细胞蛋白质水平的平衡对于维持正常的生理功能至关重要。USP5 属于去泛素化酶 (DUBs)家族，控制蛋白质降解并维持细胞蛋白质内稳。USP5 的异常表达与多种疾病有关，包括癌症、神经退行性疾病和炎症性疾病。在本文中，采用多层次虚拟筛选 (VS) 方法靶向 USP5 的锌指泛素结合域 (ZnF-UBD)，从而鉴定出一种很有前途的候选化合物 0456-0049。然后进行分子动力学 (MD) 模拟，以评估复合物结合的稳定性并预测相互作用中的热点残基。结果表明，候选化合物通过与残基 ARG221、TRP209、GLY220、ASN207、TYR261、TYR259 和 MET266 的关键相互作用稳定地结合到 USP5 的 ZnF-UBD 上。结合自由能计算和伞状采样 (US) 模拟突出了候选物相对于已知抑制剂的优越结合亲和力。此外，US 模拟揭示了配体解离过程中 USP5 的构象变化。这些见解为开发针对 USP5 的新型抑制剂提供了有价值的基础。
