New binding site conformations of the dengue virus NS3 protease accessed by molecular dynamics simulation.
New binding site conformations of the dengue virus NS3 protease accessed by molecular dynamics simulation.
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DOI：
10.1371/journal.pone.0072402
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Santana JM
中科院分区：
文献类型：
--
作者：
de Almeida H;Bastos IM;Ribeiro BM;Maigret B;Santana JM
登革热是由四种不同血清型的登革热病毒（DENV 1 -4）引起的，估计每年影响超过5亿人。目前，没有针对这种疾病的疫苗或抗病毒治疗。在对抗登革热的可能靶点中，有一种是病毒NS 3蛋白酶（NS 3 PRO），它在一定程度上负责病毒的加工和复制。目前，人们普遍认为，虚拟筛选活动应考虑目标蛋白的灵活性，通过使用多种活性构象状态。DENV NS 3 PRO的灵活性可以解释先前虚拟筛选研究的相对较低成功率。在这第一项工作中，我们探讨了从分子动力学（MD）模拟获得的DENV NS 3 PRO构象状态，以考虑虚拟筛选/对接过程中的蛋白酶灵活性。为此，我们通过多模板同源建模构建了完整的NS 3 PRO模型。该模型包含NS 2B辅因子（对NS 3 PRO活化至关重要）、甘氨酸柔性连接和蛋白水解结构域。MD模拟的目的是在抑制剂结合之前尽可能接近地对配体结合位点构象景观进行采样。所获得的构象MD样品被聚类成四个家庭，连同主成分分析的轨迹，证明蛋白质的灵活性。这些结果允许描述Bz-Nle-Lys-Arg-Arg-H抑制剂的多种结合模式，如通过结合图和对相互作用分析所验证的。这项研究使我们能够在针对登革热病毒NS 3蛋白酶的虚拟筛选活动中解决蛋白质的灵活性。
Dengue fever is caused by four distinct serotypes of the dengue virus (DENV1-4), and is estimated to affect over 500 million people every year. Presently, there are no vaccines or antiviral treatments for this disease. Among the possible targets to fight dengue fever is the viral NS3 protease (NS3PRO), which is in part responsible for viral processing and replication. It is now widely recognized that virtual screening campaigns should consider the flexibility of target protein by using multiple active conformational states. The flexibility of the DENV NS3PRO could explain the relatively low success of previous virtual screening studies. In this first work, we explore the DENV NS3PRO conformational states obtained from molecular dynamics (MD) simulations to take into account protease flexibility during the virtual screening/docking process. To do so, we built a full NS3PRO model by multiple template homology modeling. The model comprised the NS2B cofactor (essential to the NS3PRO activation), a glycine flexible link and the proteolytic domain. MD simulations had the purpose to sample, as closely as possible, the ligand binding site conformational landscape prior to inhibitor binding. The obtained conformational MD sample was clustered into four families that, together with principal component analysis of the trajectory, demonstrated protein flexibility. These results allowed the description of multiple binding modes for the Bz-Nle-Lys–Arg–Arg-H inhibitor, as verified by binding plots and pair interaction analysis. This study allowed us to tackle protein flexibility in our virtual screening campaign against the dengue virus NS3 protease.
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影响因子：
16.8
作者：
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