Abstract
Because transient receptor potential ankyrin 1 (TRPA1) is involved in various physiological functions, TRPA1-targeting drugs have been energetically developed. Although TRPA1 is considered a multimodal receptor, the structural diversity of TRPA1 agonists is not fully elucidated. We hypothesized that collecting a wider variation of TRPA1–compound interaction data would aid the understanding of its complex mechanism and aimed to challenge such data collection using an “image-based TRPA1 assay system combined with an in silico chemical space clustering concept.” Our library was clustered with 27 physicochemical molecular descriptors in silico, and structurally diverse compounds from each cluster were selected for a detailed kinetic assay to investigate variations of agonist structural rules. Through two sets of assays evaluating various compounds in parallel with validating effects of the previously established structural rules, we discovered that different chemical groups contribute to agonist activity, indicating that there are multiple agonist design concepts. A novel core structure for a TRPA1 agonist has been also proposed. Our new approach, “collection of TRPA1 activity data on compounds with physicochemical diversity,” will not only facilitate the understanding of the structural diversity of TRPA1 agonists but also contribute to the development of a new type of TRPA1-targeting drug.
Highlights
IntroductionTransient receptor potential ankyrin 1 (TRPA1) is a Ca2+ -permeable cation channel expressed in sensory neurons and non-neuronal cells of different tissues
transient receptor potential ankyrin 1 (TRPA1) agonists have been widely studied for finding several interaction rules, further understanding of TRPA1 agonist interaction facilitates better agonist design
In this study, we hypothesized that collecting various TRPA1 agonists would provide novel insights for understanding the receptor–agonist interaction and the design of agonist structures
Summary
Transient receptor potential ankyrin 1 (TRPA1) is a Ca2+ -permeable cation channel expressed in sensory neurons and non-neuronal cells of different tissues. Because TRPA1 is a prospective target for treating obesity, diabetes, and atherosclerosis, and others, drugs regulating TRPA1 activity have been energetically developed in pharmaceutical companies. Various stimuli, such as chemicals, temperature, and pH, activate TRPA1. Several chemical agonists for TRPA1 have been reported, including allyl isothiocyanate (derived from mustard oil), cinnamaldehyde (derived from cinnamon), piperine (derived from pepper), and menthol (derived from mint) [1,3]. Since TRPA1 was proposed as a multimodal receptor, multiple interaction mechanisms and positions have been discovered; interaction rules have yet to be clarified
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