Fast Screening of Inhibitor Binding/Unbinding Using Novel Software Tool CaverDock
Fast Screening of Inhibitor Binding/Unbinding Using Novel Software Tool CaverDock
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DOI：
10.3389/fchem.2019.00709
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发表时间：
2019-10-29
影响因子：
5.5
通讯作者：
Damborsky, Jiri
中科院分区：
文献类型：
--
作者：
Pinto, Gaspar P.;Vavra, Ondrej;Damborsky, Jiri
蛋白质隧道和通道是药物设计的有吸引力的目标。阻断底物进入或产物释放的药物分子可以是生物活性的有效调节剂。在这里，我们展示了一个新开发的软件工具CaverDock的适用性，用于筛选数据库中的药物，对药物相关的目标。首先，我们评估了刚性和柔性侧链对七种不同蛋白质的底物和抑制剂的影响。为了评估我们的软件的准确性，我们比较了从CaverDock计算获得的结果与先前收集的热休克蛋白90 α的实验数据。最后，我们用一组FDA批准的肿瘤和抗炎药物测试了CaverDock的虚拟筛选能力，这些药物具有两个分子靶点-细胞色素P450 17 A1和白三烯A4水解酶/氨基肽酶。使用四个处理器计算刚性轨迹平均每个分子花费53分钟，其中90%成功计算。筛选确定功能隧道的基础上结合和未结合的轨迹的势能的配置文件。我们的结论是，CaverDock是一个足够快速，强大，准确的工具，用于筛选具有埋藏功能位点的非重要靶点的结合/解结合过程。CaverDock的独立版本可以在www.example.com上免费获得，网络版本可以在www.example.com上获得。https://loschmidt.chemi.muni.cz/caverweb/https://loschmidt.chemi.muni.cz/caverdock/and
Protein tunnels and channels are attractive targets for drug design. Drug molecules that block the access of substrates or release of products can be efficient modulators of biological activity. Here, we demonstrate the applicability of a newly developed software tool CaverDock for screening databases of drugs against pharmacologically relevant targets. First, we evaluated the effect of rigid and flexible side chains on sets of substrates and inhibitors of seven different proteins. In order to assess the accuracy of our software, we compared the results obtained from CaverDock calculation with experimental data previously collected with heat shock protein 90 alpha. Finally, we tested the virtual screening capabilities of CaverDock with a set of oncological and anti-inflammatory FDA-approved drugs with two molecular targets-cytochrome P450 17A1 and leukotriene A4 hydrolase/aminopeptidase. Calculation of rigid trajectories using four processors took on average 53 min per molecule with 90% successfully calculated cases. The screening identified functional tunnels based on the profile of potential energies of binding and unbinding trajectories. We concluded that CaverDock is a sufficiently fast, robust, and accurate tool for screening binding/unbinding processes of pharmacologically important targets with buried functional sites. The standalone version of CaverDock is available freely at https://loschmidt.chemi.muni.cz/caverdock/and the web version at https://loschmidt.chemi.muni.cz/caverweb/.