Identification of a new class of non-electrophilic TRPA1 agonists by a structure-based virtual screening approach

• Published in: Bioorganic & medicinal chemistry letters Vol. 30; no. 11; p. 127142
• Main Authors: Araki, Mitsugu, Kanda, Naoto, Iwata, Hiroaki, Sagae, Yukari, Masuda, Katsuyoshi, Okuno, Yasushi
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2020
• Subjects: Binding Sites; Biological Products - chemistry; Biological Products - metabolism; Hexanols - chemistry; Hexanols - metabolism; Humans; Molecular docking; Molecular Docking Simulation; Molecular Dynamics Simulation; Non-electrophilic agonists; Protein Structure, Tertiary; Structure-based virtual screening; TRPA1; TRPA1 Cation Channel - agonists; TRPA1 Cation Channel - metabolism; TRPA1; Non-electrophilic agonists; Structure-based virtual screening; MD; RMSF; MM-PBSA; Molecular dynamics simulation; Molecular docking; AUC
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2020.127142

[Display omitted] Recent work has gradually been clarifying the binding site of non-electrophilic agonists on the transient receptor potential A1 (TRPA1). This study searched for non-electrophilic TRPA1 agonists by means of in silico drug discovery techniques based on three-dimensional (3-D) protein structure. First, agonist-bound pocket structures were explored using an advanced molecular dynamics simulation starting from the cryo-electron microscopic structure of TRPA1, and several pocket structures suitable for virtual screening were extracted by structure evaluation using known non-electrophilic TRPA1 agonists. Next, 49 compounds were selected as new non-electrophilic agonist candidates from a library of natural products comprising 10,555 compounds by molecular docking toward these pocket structures. Measurement of the TRPA1 agonist activity of these compounds showed notable TRPA1 activation with three compounds (decanol, 2-ethyl-1-hexanol, phenethyl butanoate). Decanol and 2-ethyl-1-hexanol, which are categorized as fatty alcohols, in particular have a novel chemical scaffold for TRPA1 activation. The results of this study are expected to be of considerable use in understanding the molecular mechanism of TRPA1 recognition by non-electrophilic agonists.