Wu Jiadai, Power Helen, Miranda-Saksena Monica, Valtchev Peter, Schindeler Aaron, Cunningham Anthony L, Dehghani Fariba
School of Chemical and Biomolecular Engineering, Faculty of Engineering, The University of Sydney, Sydney 2006, Australia.
Centre for Advanced Food Engineering, The University of Sydney, Sydney 2006, Australia.
Pharmaceuticals (Basel). 2022 Mar 16;15(3):361. doi: 10.3390/ph15030361.
Herpes simplex virus (HSV) infections are a worldwide health problem in need of new effective treatments. Of particular interest is the identification of antiviral agents that act via different mechanisms compared to current drugs, as these could interact synergistically with first-line antiherpetic agents to accelerate the resolution of HSV-1-associated lesions. For this study, we applied a structure-based molecular docking approach targeting the nectin-1 and herpesvirus entry mediator (HVEM) binding interfaces of the viral glycoprotein D (gD). More than 527,000 natural compounds were virtually screened using Autodock Vina and then filtered for favorable ADMET profiles. Eight top hits were evaluated experimentally in African green monkey kidney cell line (VERO) cells, which yielded two compounds with potential antiherpetic activity. One active compound (1-(1-benzofuran-2-yl)-2-[(5Z)-2H,6H,7H,8H-[1,3] dioxolo[4,5-g]isoquinoline-5-ylidene]ethenone) showed weak but significant antiviral activity. Although less potent than antiherpetic agents, such as acyclovir, it acted at the viral inactivation stage in a dose-dependent manner, suggesting a novel mode of action. These results highlight the feasibility of in silico approaches for identifying new antiviral compounds, which may be further optimized by medicinal chemistry approaches.
单纯疱疹病毒（HSV）感染是一个全球性的健康问题，需要新的有效治疗方法。特别值得关注的是鉴定与现有药物作用机制不同的抗病毒药物，因为这些药物可能与一线抗疱疹药物协同作用，加速HSV-1相关损伤的消退。在本研究中，我们应用了一种基于结构的分子对接方法，靶向病毒糖蛋白D（gD）的nectin-1和疱疹病毒进入介质（HVEM）结合界面。使用Autodock Vina对超过527,000种天然化合物进行虚拟筛选，然后根据良好的药物代谢动力学（ADMET）特性进行筛选。在非洲绿猴肾细胞系（VERO）细胞中对8种最佳命中化合物进行了实验评估，结果得到了两种具有潜在抗疱疹活性的化合物。一种活性化合物（1-(1-苯并呋喃-2-基)-2-[(5Z)-2H,6H,7H,8H-[1,3]二氧杂环戊烯并[4,5-g]异喹啉-5-亚基]乙烯酮）显示出较弱但显著的抗病毒活性。虽然其效力不如阿昔洛韦等抗疱疹药物，但它在病毒灭活阶段呈剂量依赖性作用，提示了一种新的作用模式。这些结果突出了通过计算机方法鉴定新抗病毒化合物的可行性，这些化合物可能通过药物化学方法进一步优化。
