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Computational assessment of TRPA1 interaction with 4-hydroxynonenal
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1  Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Splaiul Independentei, No 91-95, 050095, Bucharest, Romania
Academic Editor: Duke Wang

Published: 01 November 2023 by MDPI in 9th International Electronic Conference on Medicinal Chemistry session General

TRPA1 is a transient receptor potential (TRP) cation channel superfamily member. These receptors have a role in many processes like inflammation, metabolism, sensation, and tumorigenesis. Previous studies showed that TRPA1 can form adducts with reactive aldehydes, which trigger the release of pro-inflammatory mediators. The reactive aldehydes can be exogenous, from alcohol or tobacco consumption, or can result from lipid peroxidation under oxidative stress conditions.

We show in our preliminary studies, using Ca2+ microfluorimetry, that 4-hydroxynonenal (4-HNE) stimulates Ca2+ uptake by TRPA1. 4-HNE is an endogenous aldehyde with an essential role in both physiological and pathological processes. To further elucidate this effect, we used molecular docking methods to investigate the interaction of human TRPA1 with 4-HNE.

Initially, we confirmed the affinity of 4-HNE for the expected binding site represented by the cysteine pocket, including Cys621, the main residue involved in the binding of covalent ligands. Covalent docking simulations between Cys621 and HNE were performed to obtain possible adduct conformations. The best poses will be analyzed by molecular dynamics to understand the mechanism by which HNE modulates TRPA1 activity. The obtained data would provide insight into possible future pharmacological strategies for targeting the interaction between TRP channels and reactive aldehydes in pathologic conditions.

Keywords: TRPA1;4-hydroxynonenal;Inflammation;Endogenous aldehydes