Discovery of novel covalent inhibitors of DJ-1 through hybrid virtual screening
- Future Med Chem. 2024 Apr;16(7):665-677. doi: 10.4155/fmc-2023-0301.
- 1. Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai, China.
- 2. Innovation Center for AI & Drug Discovery, East China Normal University, Shanghai, 200062, China.
- 3. Lingang Laboratory, Shanghai, 200031, China.
Background: DJ-1 is a ubiquitously expressed protein with multiple functions. Its overexpression has been associated with the occurrence of several cancers, positioning DJ-1 as a promising therapeutic target for Cancer treatment. Methods: To find novel inhibitors of DJ-1, we employed a hybrid virtual screening strategy that combines structure-based and ligand-based virtual screening on a comprehensive compound library. Results: In silico study identified six hit compounds as potential DJ-1 inhibitors that were assessed in vitro at the cellular level. Compound 797780-71-3 exhibited antiproliferation activity in ACHN cells with an IC50 value of 12.18 μM and was able to inhibit the Wnt signaling pathway. This study discovers a novel covalent inhibitor for DJ-1 and paves the way for further optimization.