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<p>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.</p> Graphical Abstract <p></p>

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Structure-based discovery of novel non-covalent small molecule inhibitors of USP30

  • 期刊论文

  • 发表日期：

    2025年4月25日

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  • Padmanabhan Anbazhagan,
  • Jothi Anantharajan,
  • Justina Fulwood,
  • Choon Heng Low,
  • Nithya Baburajendran,
  • Klement Foo,
  • Weijun Xu

摘要

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.

Graphical Abstract