人类和牲畜的土壤传播的蠕虫感染会导致严重的虚弱,降低全球生产率和经济损失。治疗蠕虫感染的有效驱虫药物数量有限,它们的频繁使用导致了许多寄生虫物种的抗性发展。迫切需要用于治疗这些寄生虫的新型治疗药物。我们已经选择了ACR-16烟碱乙酰胆碱受体的蛔虫(Asu-ACR-16),作为药物靶标,并开发了这种跨膜蛋白受体的三维模型,以促进寻找新的生物活性化合物。使用人类α7nAChR嵌合体和鱼雷nAChR进行同源性建模,我们在Asu-ACR-16受体上定义了正构和变构结合位点,用于虚拟筛选.我们鉴定了与Asu-ACR-16上的位点结合的四种配体,并使用来自非洲爪的卵母细胞中表达的Asu-ACR-16受体的电生理记录测试了它们的活性。四种配体是乙酰胆碱抑制剂(SB-277011-A,IC50,3.12±1.29μM;(+)-丁胺醇Cl,IC50,9.85±2.37μM;fmoc-1,IC50,10.00±1.38μM;fmoc-2,IC50,16.67±1.95μM),表现类似负变构调节剂。我们的工作说明了一种基于结构的计算机筛选方法,用于寻找驱虫药命中,然后可以进行电生理测试以进一步表征。
Soil-transmitted helminth infections in humans and livestock cause significant debility, reduced productivity and economic losses globally. There are a limited number of effective anthelmintic drugs available for treating helminths infections, and their frequent use has led to the development of resistance in many parasite species. There is an urgent need for novel therapeutic drugs for treating these parasites. We have chosen the ACR-16 nicotinic acetylcholine receptor of Ascaris suum (Asu-ACR-16), as a drug target and have developed three-dimensional models of this transmembrane protein receptor to facilitate the search for new bioactive compounds. Using the human α7 nAChR chimeras and Torpedo marmorata nAChR for homology modeling, we defined orthosteric and allosteric binding sites on the Asu-ACR-16 receptor for virtual screening. We identified four ligands that bind to sites on Asu-ACR-16 and tested their activity using electrophysiological recording from Asu-ACR-16 receptors expressed in Xenopus oocytes. The four ligands were acetylcholine inhibitors (SB-277011-A, IC50, 3.12 ± 1.29 μM; (+)-butaclamol Cl, IC50, 9.85 ± 2.37 μM; fmoc-1, IC50, 10.00 ± 1.38 μM; fmoc-2, IC50, 16.67 ± 1.95 μM) that behaved like negative allosteric modulators. Our work illustrates a structure-based in silico screening method for seeking anthelmintic hits, which can then be tested electrophysiologically for further characterization.