Universidade Estadual Paulista, Departamento de Física e Química, Faculdade de Engenharia de Ilha Solteira, Ilha Solteira, SP, Brazil; Faculdade de Medicina, Centro Universitário de Santa Fé do Sul - UNIFUNEC, Santa Fé do Sul, SP, Brazil.
Universidade Federal de Minas Gerais, Instituto de Ciências Agrícolas, Montes Claros, MG, Brazil.
Vet Parasitol. 2023 Sep;321:110001. doi: 10.1016/j.vetpar.2023.110001. Epub 2023 Aug 1.
In vitro larvicidal assays carried out previously by our research group with cubebin, dihydrocubebin and hinokinin, lignans extracted from the fruits of Piper cubeba, against Haemonchus contortus larvae showed strong action larvicidal these compounds. Hinokinin was the most active (EC = 0.34 µg/mL) with strong action on the cuticle of the larvae as observed by scanning electron microscopy of the L3 stage. Therefore, to understand the mechanism of action of these compounds in silico studies were carried out using the enzyme phosphomethyltransferase of Haemonchus contortus that contain PMT-1 and PMT-2 di-domains responsible for phosphocholine synthesis, which is one of the main lipids in nematodes. This pathway is not found in mammals, so this enzyme is an important biological target for the development of new anthelmintics. Results of molecular docking, molecular dynamic and a density functional theory calculations studies with the three lignans show few interactions with PMT-1. However, hinokinin has important interactions with PMT-2, that can deactivate the enzyme and interrupt the phosphocholine synthesis, which is an essential compound for the development and maintenance of the nematode cuticle and its survive. Therefore, the previous results of the in vitro assay allied with in silico results, now realized; suggest that hinokinin may be a possible selective target for the development of new anthelmintics against Haemonchus contortus since the PMT-2 domain is present in this nematode.
我们研究小组之前曾用荜澄茄中的毕澄茄素、二氢毕澄茄素和柏木脑对旋毛虫幼虫进行了体外杀虫试验，结果表明这些化合物具有很强的杀虫活性。柏木脑活性最强（EC = 0.34 µg/mL），对 L3 期幼虫的角质层有强烈作用，通过扫描电子显微镜观察到这一点。因此，为了了解这些化合物的作用机制，我们在计算机上对旋毛虫的磷酸甲基转移酶进行了研究，该酶包含 PMT-1 和 PMT-2 两个结构域，负责磷酸胆碱的合成，这是线虫中主要脂质之一。这种途径在哺乳动物中不存在，因此这种酶是开发新型驱虫药的重要生物靶标。与三种木脂素进行分子对接、分子动力学和密度泛函理论计算的研究结果表明，它们与 PMT-1 的相互作用很少。然而，柏木脑与 PMT-2 有重要的相互作用，可以使酶失活并中断磷酸胆碱的合成，这是线虫角质层及其存活所必需的化合物。因此，体外试验的先前结果与现在实现的计算机结果一致，表明柏木脑可能是开发针对旋毛虫的新型驱虫药的一个有希望的靶标，因为 PMT-2 结构域存在于这种线虫中。
