Structure-based virtual screening workflow to identify antivirals targeting HIV-1 capsid.
Structure-based virtual screening workflow to identify antivirals targeting HIV-1 capsid.
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DOI：
10.1007/s10822-022-00446-5
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发表时间：
2022-03
影响因子：
3.5
通讯作者：
Levy R
中科院分区：
文献类型：
--
作者：
Sun Q;Biswas A;Vijayan RSK;Craveur P;Forli S;Olson AJ;Castaner AE;Kirby KA;Sarafianos SG;Deng N;Levy R
我们已经确定了针对PF74结合位点的新型HIV-1衣壳蛋白抑制剂。作为HIV-1衣壳核心的构建块，HIV-1衣壳蛋白在病毒生命周期中发挥着重要作用，是抗病毒开发的一个有吸引力的靶点。基于结构的虚拟筛选工作流程用于HIT鉴定，其中包括将160万种商业上可获得的类药物化合物从锌数据库对接到衣壳二聚体，然后对对接的500个排名靠前的分子应用两个绝对结合自由能(ABFE)过滤器。第一种采用隐式溶剂中的结合能分布分析方法(BEDAM)。然后在显性溶剂中使用双去偶联方法精制排名靠前的化合物。对接和BEDAM改进都是在IBM世界社区网格上进行的，作为FightAIDS@Home项目的一部分。使用这个虚拟筛选流程，我们识别了24个分子，其结合自由能计算在 − 6和 − 12千卡/摩尔之间。我们对这些分子进行了热位移分析，以检测它们对HIV-1衣壳六聚体稳定性的潜在影响，发现两个化合物ZINC520357473和ZINC4119064使后者的熔点分别提高了14.8℃和33℃。这些结果支持这两个锌化合物是针对衣壳二聚体界面的主要靶点的结论。我们的模拟还表明，这两个撞击分子可能通过占据一个新的子囊而结合在衣壳二聚体界面上，而现有的CA抑制剂还没有利用这个子囊。讨论了ABFE过滤器建议的其他得分最高的化合物未能显示可测量的活性的可能原因。网上版载有补充材料，可在10.1007/s10822-022-00446-5查阅。
We have identified novel HIV-1 capsid inhibitors targeting the PF74 binding site. Acting as the building block of the HIV-1 capsid core, the HIV-1 capsid protein plays an important role in the viral life cycle and is an attractive target for antiviral development. A structure-based virtual screening workflow for hit identification was employed, which includes docking 1.6 million commercially-available drug-like compounds from the ZINC database to the capsid dimer, followed by applying two absolute binding free energy (ABFE) filters on the 500 top-ranked molecules from docking. The first employs the Binding Energy Distribution Analysis Method (BEDAM) in implicit solvent. The top-ranked compounds are then refined using the Double Decoupling method in explicit solvent. Both docking and BEDAM refinement were carried out on the IBM World Community Grid as part of the FightAIDS@Home project. Using this virtual screening workflow, we identified 24 molecules with calculated binding free energies between − 6 and − 12 kcal/mol. We performed thermal shift assays on these molecules to examine their potential effects on the stability of HIV-1 capsid hexamer and found that two compounds, ZINC520357473 and ZINC4119064 increased the melting point of the latter by 14.8 °C and 33 °C, respectively. These results support the conclusion that the two ZINC compounds are primary hits targeting the capsid dimer interface. Our simulations also suggest that the two hit molecules may bind at the capsid dimer interface by occupying a new sub-pocket that has not been exploited by existing CA inhibitors. The possible causes for why other top-scored compounds suggested by ABFE filters failed to show measurable activity are discussed. The online version contains supplementary material available at 10.1007/s10822-022-00446-5.
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影响因子：
4.6
作者：
Heinzelmann G;Gilson MK
通讯作者：
Gilson MK
影响因子：
6.7
作者：
Blair WS;Pickford C;Irving SL;Brown DG;Anderson M;Bazin R;Cao J;Ciaramella G;Isaacson J;Jackson L;Hunt R;Kjerrstrom A;Nieman JA;Patick AK;Perros M;Scott AD;Whitby K;Wu H;Butler SL
通讯作者：
Butler SL
DOI：
10.1073/pnas.1419945112
发表时间：
2014-12-30
影响因子：
11.1
作者：
Bhattacharya, Akash;Alam, Steven L.;Yeager, Mark
通讯作者：
Yeager, Mark
影响因子：
4.1
作者：
He, Xibing;Liu, Shuhan;Wang, Junmei
通讯作者：
Wang, Junmei
影响因子：
2.9
作者：
Felts, AK;Harano, Y;Levy, RM
通讯作者：
Levy, RM