Open AccessDeglycase-activity oriented screening to identify DJ-1 inhibitors
Author(s) -
Igor Maksimovic,
Efrat Finkin-Groner,
Yoshiyuki Fukase,
Qingfei Zheng,
Shan Sun,
Mayako Michino,
David J. Huggins,
Robert W. Myers,
Yael David
Publication year - 2021
Publication title -
rsc medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.754
H-Index - 55
ISSN - 2632-8682
DOI - 10.1039/d1md00062d
Subject(s) - methylglyoxal , enzyme , biochemistry , drug discovery , chemistry , glycation , nucleotide , computational biology , biology , receptor , gene
The oncoprotein and Parkinson's disease-associated enzyme DJ-1/PARK7 has emerged as a promiscuous deglycase that can remove methylglyoxal-induced glycation adducts from both proteins and nucleotides. However, dissecting its structural and enzymatic functions remains a challenge due to the lack of potent, specific, and pharmacokinetically stable inhibitors targeting its catalytic site (including Cys106). To evaluate potential drug-like leads against DJ-1, we leveraged its deglycase activity in an enzyme-coupled, fluorescence lactate-detection assay based on the recent understanding of its deglycation mechanism. In addition, we developed assays to directly evaluate DJ-1's esterase activity using both colorimetric and fluorescent substrates. The resulting optimized assay was used to evaluate a library of potential reversible and irreversible DJ-1 inhibitors. The deglycase activity-oriented screening strategy described herein establishes a new platform for the discovery of potential anti-cancer drugs.