Discovery of a novel HIV‐1 integrase inhibitor from natural compounds through structure based virtual screening and cell imaging
Discovery of a novel HIV‐1 integrase inhibitor from natural compounds through structure based virtual screening and cell imaging
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DOI：
10.1016/j.febslet.2014.08.004
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发表时间：
2014-09
期刊：
影响因子：
3.5
通讯作者：
W. Gu;Xuan Zhang;D. Ip;Liu-Meng Yang;Yong-tang Zheng;D. Wan
中科院分区：
文献类型：
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作者：
W. Gu;Xuan Zhang;D. Ip;Liu-Meng Yang;Yong-tang Zheng;D. Wan
HIV-1整合酶与LEDGF/P75之间的相互作用已被证实为抗HIV药物开发的靶点。基于整合酶与LEDGF/P75复合物的晶体结构，采用虚拟筛选法筛选了包含8万个天然化合物的文库。选择11个命中物用于基于细胞的测定。一种化合物3-（1，3-苯并噻唑-2-基）-8-{[双（2-羟乙基）氨基]甲基}-7-羟基-2H-色烯-2-酮（D 719）在细胞成像中抑制整合酶核转位。通过分子模拟分析了D 719的结合模式。通过测定急性感染时p24抗原的产生来检测D 719的抗HIV活性。D 719的结构特征可为整合酶抑制剂的设计提供有价值的信息。
The interaction between HIV-1 integrase and LEDGF/P75 has been validated as a target for anti-HIV drug development. Based on the crystal structure of integrase in complex with LEDGF/P75, a library containing 80 thousand natural compounds was filtered with virtual screening. 11 hits were selected for cell based assays. One compound, 3-(1,3-benzothiazol-2-yl)-8-{[bis(2-hydroxyethyl)amino]methyl}-7-hydroxy-2H-chromen-2-one (D719) inhibited integrase nuclear translocation in cell imaging. The binding mode of D719 was analyzed with molecular simulation. The anti-HIV activity of D719 was assayed by measuring the p24 antigen production in acute infection. The structure characteristics of D719 may provide valuable information for integrase inhibitor design.