Department of Chemistry & Biochemistry, University of Oklahoma, OK, USA.
Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Mumbai, India.
J Biomol Struct Dyn. 2021 Oct;39(16):6306-6316. doi: 10.1080/07391102.2020.1796811. Epub 2020 Jul 22.
Spike glycoprotein, a class I fusion protein harboring the surface of SARS-CoV-2 (SARS-CoV-2S), plays a seminal role in the viral infection starting from recognition of the host cell surface receptor, attachment to the fusion of the viral envelope with the host cells. Spike glycoprotein engages host Angiotensin-converting enzyme 2 (ACE2) receptors for entry into host cells, where the receptor recognition and attachment of spike glycoprotein to the ACE2 receptors is a prerequisite step and key determinant of the host cell and tissue tropism. Binding of spike glycoprotein to the ACE2 receptor triggers a cascade of structural transitions, including transition from a metastable pre-fusion to a post-fusion form, thereby allowing membrane fusion and internalization of the virus. From ancient times people have relied on naturally occurring substances like phytochemicals to fight against diseases and infection. Among these phytochemicals, flavonoids and non-flavonoids have been the active sources of different anti-microbial agents. We performed molecular docking studies using 10 potential naturally occurring compounds (flavonoids/non-flavonoids) against the SARS-CoV-2 spike protein and compared their affinity with an FDA approved repurposed drug hydroxychloroquine (HCQ). Further, our molecular dynamics (MD) simulation and energy landscape studies with fisetin, quercetin, and kamferol revealed that these molecules bind with the hACE2-S complex with low binding free energy. The study provided an indication that these molecules might have the potential to perturb the binding of hACE2-S complex. In addition, ADME analysis also suggested that these molecules consist of drug-likeness property, which may be further explored as anti-SARS-CoV-2 agents. Communicated by Ramaswamy H. Sarma.
刺突糖蛋白是一种 I 类融合蛋白，它携带着 SARS-CoV-2（SARS-CoV-2S）的表面，在病毒感染中起着重要作用，从识别宿主细胞表面受体开始，到病毒包膜与宿主细胞融合。刺突糖蛋白通过与宿主血管紧张素转换酶 2（ACE2）受体结合进入宿主细胞，其中受体识别和刺突糖蛋白与 ACE2 受体的结合是进入宿主细胞和组织的先决条件和关键决定因素。刺突糖蛋白与 ACE2 受体的结合触发了一系列结构转变，包括从亚稳态的预融合形式转变为融合后的形式，从而允许病毒膜融合和内化。自古以来，人们就依赖于天然存在的物质，如植物化学物质，来对抗疾病和感染。在这些植物化学物质中，类黄酮和非类黄酮一直是不同抗菌剂的活性来源。我们使用 10 种潜在的天然化合物（类黄酮/非类黄酮）对 SARS-CoV-2 刺突蛋白进行了分子对接研究，并将它们与 FDA 批准的重新利用药物羟氯喹（HCQ）的亲和力进行了比较。此外，我们对非瑟酮、槲皮素和香豆素进行了分子动力学（MD）模拟和能量景观研究，结果表明这些分子与 hACE2-S 复合物的结合具有较低的结合自由能。该研究表明，这些分子可能具有干扰 hACE2-S 复合物结合的潜力。此外，ADME 分析还表明，这些分子具有药物相似性的特性，可能会进一步作为抗 SARS-CoV-2 药物进行探索。由 Ramaswamy H. Sarma 传达。
