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Identification of a new class of non-electrophilic TRPA1 agonists by a structure-based virtual screening approach.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-03-26 , DOI: 10.1016/j.bmcl.2020.127142 Mitsugu Araki 1 , Naoto Kanda 2 , Hiroaki Iwata 1 , Yukari Sagae 1 , Katsuyoshi Masuda 3 , Yasushi Okuno 1
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-03-26 , DOI: 10.1016/j.bmcl.2020.127142 Mitsugu Araki 1 , Naoto Kanda 2 , Hiroaki Iwata 1 , Yukari Sagae 1 , Katsuyoshi Masuda 3 , Yasushi Okuno 1
Affiliation
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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.
中文翻译：
通过基于结构的虚拟筛选方法鉴定一类新的非亲电子TRPA1激动剂。
最近的工作已逐渐阐明非亲电子激动剂在瞬时受体电位A1（TRPA1）上的结合位点。这项研究通过基于三维（3-D）蛋白结构的计算机内药物发现技术，寻找非亲电子性TRPA1激动剂。首先，使用先进的分子动力学模拟从TRPA1的低温电子微观结构开始探索与激动剂结合的口袋结构，然后使用已知的非亲电子TRPA1激动剂通过结构评估提取一些适合虚拟筛选的口袋结构。接下来，通过分子对接这些口袋结构的方式，从包含10,555种化合物的天然产物库中选择了49种化合物作为新的非亲电子激动剂候选物。对这些化合物的TRPA1激动剂活性的测量显示了三种化合物（癸醇，2-乙基-1-己醇，丁酸苯乙酯）的显着TRPA1活化。归类为脂肪醇的癸醇和2-乙基-1-己醇特别具有用于TRPA1活化的新型化学支架。预期该研究的结果将在理解非亲电激动剂识别TRPA1的分子机理方面有相当大的用途。
更新日期：2020-04-20
中文翻译：
通过基于结构的虚拟筛选方法鉴定一类新的非亲电子TRPA1激动剂。
最近的工作已逐渐阐明非亲电子激动剂在瞬时受体电位A1（TRPA1）上的结合位点。这项研究通过基于三维（3-D）蛋白结构的计算机内药物发现技术，寻找非亲电子性TRPA1激动剂。首先，使用先进的分子动力学模拟从TRPA1的低温电子微观结构开始探索与激动剂结合的口袋结构，然后使用已知的非亲电子TRPA1激动剂通过结构评估提取一些适合虚拟筛选的口袋结构。接下来，通过分子对接这些口袋结构的方式，从包含10,555种化合物的天然产物库中选择了49种化合物作为新的非亲电子激动剂候选物。对这些化合物的TRPA1激动剂活性的测量显示了三种化合物（癸醇，2-乙基-1-己醇，丁酸苯乙酯）的显着TRPA1活化。归类为脂肪醇的癸醇和2-乙基-1-己醇特别具有用于TRPA1活化的新型化学支架。预期该研究的结果将在理解非亲电激动剂识别TRPA1的分子机理方面有相当大的用途。
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