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Identification of potential drugs against SARS-CoV-2 non-structural protein 1 (nsp1)
Journal of Biomolecular Structure and Dynamics ( IF 4.4 ) Pub Date : 2020-07-13 , DOI: 10.1080/07391102.2020.1792992
Gabriela de Lima Menezes 1 , Roosevelt Alves da Silva 1
Affiliation  

Abstract

Non-structural protein 1 (nsp1) is found in all Betacoronavirus genus, an important viral group that causes severe respiratory human diseases. This protein has significant role in pathogenesis and it is considered a probably major virulence factor. As it is absent in humans, it becomes an interesting target of study, especially when it comes to the rational search for drugs, since it increases the specificity of the target and reduces possible adverse effects that may be caused to the patient. Using approaches in silico we seek to study the behavior of nsp1 in solution to obtain its most stable conformation and find possible drugs with affinity to all of them. For this purpose, complete model of nsp1 of SARS-CoV-2 were predicted and its stability analyzed by molecular dynamics simulations in five different replicas. After main pocket validation using two control drugs and the main conformations of nsp1, molecular docking based on virtual screening were performed to identify novel potential inhibitors from DrugBank database. It has been found 16 molecules in common to all five nsp1 replica conformations. Three of them was ranked as the best compounds among them and showed better energy score than control molecules that have in vitro activity against nsp1 from SARS-CoV-2. The results pointed out here suggest new potential drugs for therapy to aid the rational drug search against COVID-19.

Communicated by Ramaswamy H. Sarma



中文翻译:

鉴定针对 SARS-CoV-2 非结构蛋白 1 (nsp1) 的潜在药物

摘要

非结构蛋白 1 (nsp1) 存在于所有β冠状病毒属中,这是一个重要的病毒组,可导致严重的人类呼吸道疾病。该蛋白质在发病机理中具有重要作用,并且被认为可能是主要的毒力因子。由于它在人类中不存在,它成为一个有趣的研究目标,尤其是在合理寻找药物方面,因为它增加了目标的特异性并减少了可能对患者造成的不良反应。在计算机中使用方法我们试图研究 nsp1 在溶液中的行为以获得其最稳定的构象,并找到对所有这些都具有亲和力的可能药物。为此,预测了 SARS-CoV-2 的 nsp1 的完整模型,并通过五个不同复制品的分子动力学模拟分析了其稳定性。在使用两种对照药物和 nsp1 的主要构象进行主要口袋验证后,进行基于虚拟筛选的分子对接,以从 DrugBank 数据库中识别新的潜在抑制剂。已发现所有五个 nsp1 复制构象共有 16 个分子。其中三个被评为其中最好的化合物,并显示出比体外具有的对照分子更好的能量得分SARS-CoV-2 对 nsp1 的活性。这里指出的结果提出了新的潜在治疗药物,以帮助对 COVID-19 进行合理的药物搜索。

由 Ramaswamy H. Sarma 交流

更新日期:2020-07-13
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