Discovery of Novel Covalent Inhibitors of DJ-1 Through Hybrid Virtual Screening

Abstract

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.

Keywords::

• cancer treatment
• covalent inhibitor
• DJ-1
• molecular docking
• virtual screening

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.4155/fmc-2023-0301

Author contributions

Y Ma, Y Song and J Wang performed the experiment and drafted the manuscript. Y Ma and Y Song performed the computational experiment; J Wang and X Shi performed the bioassay; Z Yuan and S Li contributed to the discussion and writing of the manuscript. H Li contributed to data analysis. SL Li and Z Chen supervised the project. All authors discussed the results and commented on the manuscript.

Financial disclosure

This work was supported in part by the National Key R&D Program of China (2022YFC3400504); the National Natural Science Foundation of China (82173690 to S.L.L.); S.L.L. is also sponsored by the Shanghai Rising-Star Program (23QA1402800). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.