Virtual screening based identification of novel small-molecule inhibitors targeted to the HIV-1 capsid.
Virtual screening based identification of novel small-molecule inhibitors targeted to the HIV-1 capsid.
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DOI：
10.1016/j.bmc.2010.11.045
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发表时间：
2011-01-01
影响因子：
3.5
通讯作者：
Debnath, Asim K.
中科院分区：
文献类型：
--
作者：
Curreli, Francesca;Zhang, Hongtao;Zhang, Xihui;Pyatkin, Ilya;Victor, Zagorodnikov;Altieri, Andrea;Debnath, Asim K.
关键词：
HIV-1衣壳蛋白C端结构域（CTD）的疏水空腔最近被证实是基于肽的抑制剂抗病毒药物的潜在靶点;然而，还没有任何小分子化合物靶向该疏水空腔的报道。为了填补这一空白并发现新类别的抗HIV-1抑制剂，我们进行了基于对接的虚拟筛选和随后的类似物搜索，以及药物化学方法来鉴定针对该靶标的小分子抑制剂。本文报告的第一次，尽我们所知，鉴定不同类别的抑制剂，有效地抑制成熟样病毒颗粒的形成，在电子显微镜（EM）下验证，并显示出潜在的抗HIV-1药物的病毒感染性测定对广泛的实验室适应以及MT-2细胞和PBMC中的主要分离株。此外，在用两种最具活性的化合物处理HIV-1感染的细胞后产生的病毒体显示出显著降低的感染性，证实了这些化合物作为抗HIV-1剂的潜力。我们从抗病毒数据中推导出了全面的SAR。SAR分析将有助于进一步优化潜在抗HIV-1药物的线索。
The hydrophobic cavity of the C-terminal domain (CTD) of HIV-1 capsid has been recently validated as potential target for antiviral drugs by peptide-based inhibitors; however, there is no report yet of any small molecule compounds that target this hydrophobic cavity. In order to fill this gap and discover new classes of ant-HIV-1 inhibitors, we undertook a docking-based virtual screening and subsequent analog search, and medicinal chemistry approaches to identify small molecule inhibitors against this target. This article reports for the first time, to the best of our knowledge, identification of diverse classes of inhibitors that efficiently inhibited the formation of mature-like viral particles verified under electron microscope (EM) and showed potential as anti-HIV-1 agents in a viral infectivity assay against a wide range of laboratory-adapted as well as primary isolates in MT-2 cells and PBMC. In addition, the virions produced after the HIV-1 infected cells were treated with two of the most active compounds showed drastically reduced infectivity confirming the potential of these compounds as anti-HIV-1 agents. We have derived a comprehensive SAR from the antiviral data. The SAR analyses will be useful in further optimizing the leads to potential anti-HIV-1 agents.
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影响因子：
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