Anbazhagan Padmanabhan, Anantharajan Jothi, Fulwood Justina, Low Choon Heng, Baburajendran Nithya, Foo Klement, Xu Weijun
Experimental Drug Development Centre, Agency for Science, Technology and Research (A*STAR), 10 Biopolis Road, Chromos, Singapore, 138670, Singapore.
J Comput Aided Mol Des. 2025 Apr 25;39(1):19. doi: 10.1007/s10822-025-00596-2.
Ubiquitin-specific proteases (USPs) are crucial regulators of protein degradation pathways, influencing diverse cellular processes and disease mechanisms. Among them, USP30 plays a pivotal role in mitochondrial quality control and has been implicated in idiopathic pulmonary fibrosis (IPF), a chronic lung disease for which current therapies merely slow disease progression. The high flexibility of USP30's catalytic site, coupled with its dependence on covalent interaction with the catalytic cysteine presents significant challenges in discovering suitable small molecule inhibitors. In this study, we identified three non-covalent small molecule inhibitors for USP30 using molecular modeling, X-ray crystallography, and virtual screening. These findings offer valuable insights and novel chemical starting points for further medicinal chemistry optimization.
泛素特异性蛋白酶（USPs）是蛋白质降解途径的关键调节因子，影响多种细胞过程和疾病机制。其中，USP30在线粒体质量控制中起关键作用，并与特发性肺纤维化（IPF）有关，IPF是一种慢性肺病，目前的治疗方法只能减缓疾病进展。USP30催化位点的高度灵活性，加上其对与催化半胱氨酸共价相互作用的依赖性，在发现合适的小分子抑制剂方面提出了重大挑战。在本研究中，我们使用分子建模、X射线晶体学和虚拟筛选确定了三种USP30的非共价小分子抑制剂。这些发现为进一步的药物化学优化提供了有价值的见解和新的化学起始点。
