Structure-Based Identification of Kelch-like ECH-Associated Protein 1 as a Pharmacological Target of Electrophile-Containing Catechol-O-Methyltransferase Inhibitors.

ABSTRACT: Entacapone and nitecapone are electrophile-containing catechol-O-methyltransferase (COMT) inhibitors that are used to treat Parkinson's disease in combination with L-DOPA. It is desirable to investigate whether they can covalently bind to cellular protein targets using their reactive electrophilic warheads. We identified Kelch-like ECH-associated protein 1 (KEAP1), a sensor for oxidative and electrophilic stress, as a potential pharmacological target of both drugs by performing covalent-based reverse docking. We confirmed that both drugs activate nuclear factor erythroid 2-related factor 2 (NRF2) by reversibly modifying C151 on KEAP1. Both drugs can enhance the expression of growth differentiation factor 15 (GDF15) and NRF2 downstream antioxidant response element (ARE) genes, both i

SUBMITTER: Wang P 

PROVIDER: S-EPMC10928886 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature