Multiple Virtual Screening Strategies for the Discovery of Novel Compounds Active Against Dengue Virus: A Hit Identification Study
Multiple Virtual Screening Strategies for the Discovery of Novel Compounds Active Against Dengue Virus: A Hit Identification Study
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DOI：
10.3390/scipharm88010002
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发表时间：
2020-03-01
影响因子：
2.5
通讯作者：
Rungrotmongkol, Thanyada
中科院分区：
文献类型：
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作者：
Hengphasatporn, Kowit;Garon, Arthur;Rungrotmongkol, Thanyada
登革热感染是由蚊媒病毒引起的，尤其是儿童，甚至可能导致死亡。目前尚无有效的预防或治疗药物来治疗该病。登革热病毒包膜 (E) 蛋白被发现是抑制病毒感染多个步骤的有希望的靶标。基于结构的虚拟筛选已成为药物筛选过程中识别首次命中的重要技术，因为它可以减少待测化合物的数量，从而节省资源。在本研究中，药效团模型是使用常见命中方法 (CHA) 生成的，从 E 蛋白与活性抑制剂黄烷酮 (FN5Y) 复合的分子动力学 (MD) 模拟获得的轨迹开始。随后，使用 LigandScout 4.2 程序筛选各种药物数据库中的化合物。通过分子对接对获得的命中进行更详细的分析，然后对复合物进行广泛的MD模拟。然后合成该过程中排名最高的化合物，并通过实验测定测试其抑制效率。
Dengue infection is caused by a mosquito-borne virus, particularly in children, which may even cause death. No effective prevention or therapeutic agents to cure this disease are available up to now. The dengue viral envelope (E) protein was discovered to be a promising target for inhibition in several steps of viral infection. Structure-based virtual screening has become an important technique to identify first hits in a drug screening process, as it is possible to reduce the number of compounds to be assayed, allowing to save resources. In the present study, pharmacophore models were generated using the common hits approach (CHA), starting from trajectories obtained from molecular dynamics (MD) simulations of the E protein complexed with the active inhibitor, flavanone (FN5Y). Subsequently, compounds presented in various drug databases were screened using the LigandScout 4.2 program. The obtained hits were analyzed in more detail by molecular docking, followed by extensive MD simulations of the complexes. The highest-ranked compound from this procedure was then synthesized and tested on its inhibitory efficiency by experimental assays.