Identification of acridinedione scaffolds as potential inhibitor of DENV-2 C protein: An in silico strategy to combat dengue
Identification of acridinedione scaffolds as potential inhibitor of DENV-2 C protein: An in silico strategy to combat dengue
复制标题
DOI：
10.1002/jcb.30237
复制
发表时间：
2022-03-21
影响因子：
4
通讯作者：
Purohit, Rituraj
中科院分区：
文献类型：
--
作者：
Kumar, Sachin;Bhardwaj, Vijay K.;Purohit, Rituraj
登革热是一种由蚊子传播给人类的常见病毒性疾病，主要影响全球热带和亚热带国家。登革病毒（DENV）主要通过埃及伊蚊和白纹伊蚊在全球传播。登革病毒血清型2（DENV-2）是登革病毒的一种广泛流行的血清型，其引起粘膜出血和出血，这可能是致命的。在DENV-2的生命周期中，结构衣壳（DENV-2C）蛋白形成核衣壳组装体并结合病毒子代RNA。对于DENV-2成熟，核衣壳是重要组分。我们使用虚拟配体筛选来筛选出可以有效结合DENV-2C蛋白的最佳内部合成的吖啶二酮类似物（DSPD分子）。通过分子对接和动力学模拟研究，分析DSPD分子结合后对DENV-2 C蛋白的影响。我们的研究结果表明，DSPD分子与DENV-2C蛋白强烈相互作用，从分子相互作用和几个时间依赖性分子动力学驱动的分析中可以看出。此外，本研究也得到了热力学结合自由能和导向分子动力学模拟的支持。因此，我们打算表明，DSPD 3分子可以作为一个潜在的治疗分子对登革热并发症相比，共结晶抑制剂ST-148。然而，需要进一步的研究来证明DSPD 3诱导DENV-2C四聚体形成的能力。
Dengue is a prominent viral disease transmitted by mosquitoes to humans that affects mainly tropical and subtropical countries worldwide. The global spread of dengue virus (DENV) is mainly occurred by Aedes aegypti and Aedes albopictus mosquitoes. The dengue virus serotypes-2 (DENV-2) is a widely prevalent serotype of DENV, that causes the hemorrhagic fever and bleeding in the mucosa, which can be fatal. In the life cycle of DENV-2, a structural capsid (DENV-2 C) protein forms the nucleocapsid assembly and bind to the viral progeny RNA. For DENV-2 maturation, the nucleocapsid is a vital component. We used virtual ligand screening to filter out the best in-house synthesized acridinedione analogs (DSPD molecules) that could efficiently bind to DENV-2 C protein. The molecular docking and dynamics simulations studies were performed to analyze the effect of DSPD molecules on DENV-2 C protein after binding. Our findings showed that DSPD molecules strongly interacted with DENV-2 C protein, as evident from molecular interactions and several time-dependent molecular dynamics-driven analyses. Moreover, this study was also supported by the thermodynamic binding free energy and steered molecular dynamics simulations. Therefore, we intend to suggest that the DSPD3 molecule could be used as a potential therapeutic molecule against dengue complications as compared to the cocrystallized inhibitor ST-148. However, further studies are required to demonstrate the ability of DSPD3 to induce DENV-2 C tetramer formation.