Computer-Aided Discovery and Characterization of Novel Ebola Virus Inhibitors.
Computer-Aided Discovery and Characterization of Novel Ebola Virus Inhibitors.
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DOI：
10.1021/acs.jmedchem.8b00035
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发表时间：
2018-04-26
影响因子：
7.3
通讯作者：
Tropsha A
中科院分区：
文献类型：
--
作者：
Capuzzi SJ;Sun W;Muratov EN;Martínez-Romero C;He S;Zhu W;Li H;Tawa G;Fisher EG;Xu M;Shinn P;Qiu X;García-Sastre A;Zheng W;Tropsha A
埃博拉病毒（EBOV）导致严重的人类感染，缺乏有效的治疗。最近的一项筛选发现了一系列阻止埃博拉病毒样颗粒进入人体细胞的化合物。利用该筛选的数据，建立了定量构效关系（QSAR）模型，并应用于约1700万个化合物文库的虚拟筛选。实验测试102个hit，得到14个IC50值在10 μM以下的化合物，包括几种亚微摩尔抑制剂，对宿主细胞毒性的选择性超过10倍。这些已确认的热门药物包括fda批准的药物和具有非抗病毒适应症的临床候选药物，以及具有新型支架且以前没有已知生物活性的化合物。5个选定的击中物以剂量依赖的方式抑制BSL-4活的ebov感染，包括vindesine （0.34 μM）。对这些新型抗ebov化合物的进一步研究揭示了它们的作用机制，包括抑制NPC1蛋白、组织蛋白酶B/L和溶酶体功能。本研究中鉴定的化合物是迄今为止报道的最有效和最具特征的抗ebov抑制剂之一。
The Ebola virus (EBOV) causes severe human infection that lacks effective treatment. A recent screen identified a series of compounds that block EBOV-like particle entry into human cells. Using data from this screen, Quantitative Structure-Activity Relationship (QSAR) models were built and employed for virtual screening of a ~17 million compound library. Experimental testing of 102 hits yielded 14 compounds with IC50 values under 10 μM, including several sub-micromolar inhibitors, and more than 10-fold selectivity against host cytotoxicity. These confirmed hits include FDA-approved drugs and clinical candidates with non-antiviral indications, as well as compounds with novel scaffolds and no previously known bioactivity. Five selected hits inhibited BSL-4 live-EBOV infection in a dose-dependent manner, including vindesine (0.34 μM). Additional studies of these novel anti-EBOV compounds revealed their mechanisms of action, including the inhibition of NPC1 protein, cathepsin B/L, and lysosomal function. Compounds identified in this study are among the most potent and well-characterized anti-EBOV inhibitors reported to date.
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影响因子：
7.3
作者：
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通讯作者：
Simeonov A
影响因子：
64.8
作者：
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通讯作者：
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影响因子：
6
作者：
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通讯作者：
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影响因子：
4.9
作者：
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通讯作者：
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