School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
Center for Bioinformatics, Computational and Systems Biology, Pathfinder Research and Training Foundation, Greater Noida 201308, India.
Molecules. 2022 Apr 15;27(8):2562. doi: 10.3390/molecules27082562.
Zika virus (ZIKV) has been characterized as one of many potential pathogens and placed under future epidemic outbreaks by the WHO. However, a lack of potential therapeutics can result in an uncontrolled pandemic as with other human pandemic viruses. Therefore, prioritized effective therapeutics development has been recommended against ZIKV. In this context, the present study adopted a strategy to explore the lead compounds from against ZIKV via concurrent inhibition of the NS2B-NS3 protease (ZIKV) and NS5 RNA dependent RNA polymerase (ZIKV) proteins using molecular simulations. Initially, structure-based virtual screening of 44 bioflavonoids reported in against the crystal structures of targeted ZIKV proteins resulted in the identification of the top four common bioflavonoids, viz. Rutin, Nicotiflorin, Isoquercitrin, and Hyperoside. These compounds showed substantial docking energy (-7.9 to -11.01 kcal/mol) and intermolecular interactions with essential residues of ZIKV (B:His, B:Asp, and B:Ser) and ZIKV (Asp, Ile, and Asp) by comparison to the reference compounds, O7N inhibitor (ZIKV) and Sofosbuvir inhibitor (ZIKV). Besides, long interval molecular dynamics simulation (500 ns) on the selected docked poses reveals stability of the respective docked poses contributed by intermolecular hydrogen bonds and hydrophobic interactions. The predicted complex stability was further supported by calculated end-point binding free energy using molecular mechanics generalized born surface area (MM/GBSA) method. Consequently, the identified common bioflavonoids are recommended as promising therapeutic inhibitors of ZIKV and ZIKV against ZIKV for further experimental assessment.
寨卡病毒（ZIKV）已被世界卫生组织（WHO）列为众多潜在病原体之一，并将其置于未来的流行爆发之下。然而，由于其他人类大流行病毒缺乏潜在的治疗方法，可能导致无法控制的大流行。因此，建议针对 ZIKV 优先开发有效的治疗方法。在这种情况下，本研究采用了一种策略，通过分子模拟同时抑制 ZIKV 的 NS2B-NS3 蛋白酶和 ZIKV 的 NS5 RNA 依赖性 RNA 聚合酶，从 中探索针对 ZIKV 的先导化合物。最初，针对靶向 ZIKV 蛋白的晶体结构，对 中报道的 44 种生物类黄酮进行基于结构的虚拟筛选，确定了前四种常见的生物类黄酮，即芦丁、野靛碱、异槲皮苷和金丝桃苷。这些化合物与参考化合物 O7N 抑制剂（ZIKV）和 Sofosbuvir 抑制剂（ZIKV）相比，显示出与 ZIKV（B：His、B：Asp 和 B：Ser）和 ZIKV（Asp、Ile 和 Asp）的关键残基有很大的对接能（-7.9 至-11.01 kcal/mol）和分子间相互作用。此外，对所选对接构象进行的长间隔分子动力学模拟（500 ns）表明，各自对接构象的稳定性是由分子间氢键和疏水相互作用贡献的。使用分子力学广义 Born 表面面积（MM/GBSA）方法计算终点结合自由能进一步支持了预测的复合物稳定性。因此，所鉴定的常见生物类黄酮被推荐为有希望的 ZIKV 治疗抑制剂，可进一步进行实验评估。
