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Updated: Jul 1, 2025
Author Spotlight: Streamlining Protein Target Prediction and Validation via Molecular Docking and CETSA
Published on: February 23, 2024
Structure-Based Identification of Kelch-like ECH-Associated Protein 1 as a Pharmacological Target of
Ping Wang1,2, Yang Li2, Jinyi Yang3,2
1College of Life Sciences, Beijing Normal University, No. 19 Xinjiekouwai Street, Beijing 100875, China.
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 in vitro and in vivo. Furthermore, both drugs exhibit anti-inflammatory effects in an NRF2-dependent acute gout model. Our findings suggest that these two drugs could be repurposed for the treatment of NRF2-modulated inflammatory diseases, and the 3-methylene-acetylacetone group of nitecapone could serve as a new reversible covalent warhead.
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