Esam Zohreh, Akhavan Malihe, Lotfi Maryam, Bekhradnia Ahmadreza
Pharmaceutical Research Center, Student Research Committee, Department of Medicinal Chemistry, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
Department of Medicinal Chemistry, Faculty of Pharmacy, Ayatollah Amoli Branch, Islamic Azad University, Amol, Iran.
J Mol Struct. 2022 Jan 5;1247:131394. doi: 10.1016/j.molstruc.2021.131394. Epub 2021 Aug 30.
The highly contagious Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which is a newborn infectious member of the dangerous beta-coronaviruses (β-CoVs) following SARS and MERS-CoVs, can be regarded as the most significant issue afflicting the whole world shortly after December 2019. Considering CoVs as RNA viruses with a single-stranded RNA genome (+ssRNA), the critical viral enzyme RNA dependent RNA polymerase (RdRp) is a promising therapeutic target for the potentially fatal infection COVID-19. Nicotinamide riboside (NR), which is a naturally occurring analogue of Niacin (vitamin B3), is expected to have therapeutic effects on COVID-19 due to its super close structural similarity to the proven RdRp inhibitors. Thus, at the first phase of the current molecular docking and dynamics simulation studies, we targeted SARS-CoV-2 RdRp. On the next phase, SARS-CoV RdRp, human Angiotensin-converting enzyme 2, Inosine-5'-monophosphate dehydrogenase, and the SARS-CoV-2 Structural Glycoproteins Spike, Nonstructural viral protein 3-Chymotrypsin-like protease, and Papain-like protease were targeted using the docking simulation to find other possible antiviral effects of NR serendipitously. In the current study, the resulted scores from molecular docking and dynamics simulations as the primary determinative factor as well as the observed reliable binding modes have demonstrated that Nicotinamide Riboside and its active metabolite NMN can target human ACE2 and IMPDH, along with the viral S, M, PL, and on top of all, RdRp as a potential competitive inhibitor.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起的2019冠状病毒病（COVID-19）具有高度传染性，它是继SARS和中东呼吸综合征冠状病毒之后危险的β冠状病毒（β-CoVs）中的一种新型传染性病毒，可被视为2019年12月后不久困扰全球的最重要问题。冠状病毒是具有单链RNA基因组（+ssRNA）的RNA病毒，关键的病毒酶RNA依赖性RNA聚合酶（RdRp）是治疗潜在致命感染COVID-19的一个有前景的治疗靶点。烟酰胺核糖（NR）是烟酰胺（维生素B3）的天然类似物，由于其与已证实的RdRp抑制剂在结构上极为相似，预计对COVID-19有治疗作用。因此，在当前分子对接和动力学模拟研究的第一阶段，我们以SARS-CoV-2 RdRp为靶点。在下一阶段，使用对接模拟以SARS-CoV RdRp、人血管紧张素转换酶2、肌苷-5'-单磷酸脱氢酶以及SARS-CoV-2结构糖蛋白刺突蛋白、非结构病毒蛋白3-糜蛋白酶样蛋白酶和木瓜蛋白酶样蛋白酶为靶点，以意外发现NR的其他可能抗病毒作用。在本研究中，分子对接和动力学模拟得出的分数作为主要决定因素以及观察到的可靠结合模式表明，烟酰胺核糖及其活性代谢物NMN可以靶向人ACE2和IMPDH，以及病毒的S、M、PL，最重要的是，RdRp可作为潜在的竞争性抑制剂。
