Faculty of Science and Environment, Mahatma Gandhi Chitrakoot Gramodaya Vishwavidyalaya, Chitrakoot, Satna, India.
Center for Bioinformatics, Computational and System Biology, Pathfinder Research and Training Foundation, India.
J Biomol Struct Dyn. 2021 Mar;39(4):1417-1430. doi: 10.1080/07391102.2020.1734485. Epub 2020 Mar 9.
Dengue virus (DENV) serine protease enzyme, i.e. NS2B-NS3pro (non-structural protein 2B-non-structural protein 3) has been approved as prime drug target for the drug discovery against dengue infection, because of its essential role in viral replication. This study demonstrates the potential of bioflavonoids from against dengue infection using computational and experimental approach. Initially, 49 bioflavonoids reported in were collected and virtually screened on the catalytic triad of DENV protease, results in the identification of kaempferol-3-O-rutinoside (-9.555 kcal/mol), rutin (-9.324 kcal/mol), hyperoside (-7.879 kcal/mol), and epicatechin (-7.622 kcal/mol) as potent viral protease inhibitors against reference compound quercetin (-6.94 kcal/mol). Subsequently, these docked complexes were analyzed for the stability via molecular dynamics simulations and free binding energy calculations, suggested the considerable stability of selected bioflavonoids with viral protease. Additionally, density functional theory and ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) analysis indicated the least chemical reactivity and considerable medicinal properties, respectively for the screened bioflavonoids by comparison to quercetin. Accordingly, kaempferol 3-O-β-rutinoside and epicatechin were evaluated at various concentrations for cell viability (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay) and antiviral activity (focus forming unit assay) against DENV-2 strain. The antiviral assay showed dose dependent inhibition of DENV-2 infectivity by the selected compounds while maximum 77.7% and 66.2% viral inhibition were recorded for 100 µM kaempferol 3-O-β-rutinoside and 1000 µM epicatechin, respectively without significant cell toxicity. These results suggested the potential of bioflavonoids from in the development of effective drug against dengue infection.Communicated by Ramaswamy H. Sarma.
登革热病毒（DENV）丝氨酸蛋白酶酶，即 NS2B-NS3pro（非结构蛋白 2B-非结构蛋白 3）已被批准为抗登革热感染药物发现的主要药物靶点，因为它在病毒复制中起着至关重要的作用。本研究采用计算和实验方法证明了 中类黄酮用于抗登革热感染的潜力。最初，从 中收集并虚拟筛选了 49 种类黄酮，结果鉴定出槲皮素-3-O-芦丁糖苷（-9.555kcal/mol）、芦丁（-9.324kcal/mol）、圣草酚（-7.879kcal/mol）和表儿茶素（-7.622kcal/mol）是针对参考化合物槲皮素（-6.94kcal/mol）的有效病毒蛋白酶抑制剂。随后，通过分子动力学模拟和自由结合能计算分析这些对接复合物的稳定性，表明所选类黄酮与病毒蛋白酶具有相当的稳定性。此外，密度泛函理论和 ADMET（吸收、分布、代谢、排泄和毒性）分析表明，与槲皮素相比，筛选出的类黄酮具有最小的化学反应性和相当大的药用特性。因此，在不同浓度下评估了槲皮素 3-O-β-芦丁糖苷和表儿茶素的细胞活力（3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四唑溴化物测定法）和抗 DENV-2 活性（焦点形成单位测定法）。抗病毒测定结果表明，所选化合物对 DENV-2 感染具有剂量依赖性抑制作用，而 100μM 槲皮素 3-O-β-芦丁糖苷和 1000μM 表儿茶素的病毒抑制率分别高达 77.7%和 66.2%，且无明显细胞毒性。这些结果表明， 中的类黄酮具有开发抗登革热感染有效药物的潜力。由 Ramaswamy H. Sarma 传达。
