Collection of Data Variation Using a High-Throughput Image-Based Assay Platform Facilitates Data-Driven Understanding of TRPA1 Agonist Diversity
Collection of Data Variation Using a High-Throughput Image-Based Assay Platform Facilitates Data-Driven Understanding of TRPA1 Agonist Diversity
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DOI：
10.3390/app12031622
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发表时间：
2022-02-01
影响因子：
2.7
通讯作者：
Ito, Keisuke
中科院分区：
文献类型：
--
作者：
Terada, Yuko;Tanaka, Kenjiro;Ito, Keisuke
由于瞬时受体潜在锚蛋白1(TRPA1)参与多种生理功能，靶向TRPA1的药物已被大力开发。尽管TRPA1被认为是一种多通道受体，但TRPA1激动剂的结构多样性尚未完全阐明。我们假设，收集更广泛的TRPA1-化合物相互作用数据将有助于理解其复杂的机制，并旨在挑战这种数据收集使用“基于图像的TRPA1分析系统与电子化学空间聚集概念相结合”。我们的文库由27个物理化学分子描述符聚类，并从每个簇中选择结构不同的化合物进行详细的动力学分析，以研究激动剂结构规律的变化。通过两套评估不同化合物的测试，同时验证了先前建立的结构规则的效果，我们发现不同的化学基团对激动剂活性有贡献，这表明存在多个激动剂设计概念。还提出了一种新的TRPA1激动剂的核心结构。我们的新方法，“收集具有物理化学多样性的化合物的TRPA1活性数据”，不仅将有助于了解TRPA1激动剂的结构多样性，还将有助于开发一种新型的TRPA1靶向药物。
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.