9LYF

Structure-based Discovery of Novel non-Covalent Small Molecule Inhibitors of USP30

This is a non-PDB format compatible entry.

Summary for 9LYF

• Entry DOI: 10.2210/pdb9lyf/pdb
• Descriptor: Ubiquitin carboxyl-terminal hydrolase 30, 5-(3-cyanophenyl)-~{N}-[[(3~{S})-1-(iminomethyl)pyrrolidin-3-yl]methyl]-1,3,4-oxadiazole-2-carboxamide, ZINC ION, ... (4 entities in total)
• Functional Keywords: usp30, deubiquitination, covalent small molecule inhibitor, non-covalent small molecule inhibitors, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 38859.17

Authors

Anantharajan, J.,Baburajendran, N. (deposition date: 2025-02-20, release date: 2025-05-21)

Primary citation

Anbazhagan, P.,Anantharajan, J.,Fulwood, J.,Low, C.H.,Baburajendran, N.,Foo, K.,Xu, W.
Structure-based discovery of novel non-covalent small molecule inhibitors of USP30.
J.Comput.Aided Mol.Des., 39:19-19, 2025

PubMed Abstract: 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.

PubMed: 40274689
DOI: 10.1007/s10822-025-00596-2

Experimental method

X-RAY DIFFRACTION (2.58 Å)