Repurposing potential of posaconazole and grazoprevir as inhibitors of SARS-CoV-2 helicase.
Repurposing potential of posaconazole and grazoprevir as inhibitors of SARS-CoV-2 helicase.
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DOI：
10.1038/s41598-021-89724-0
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发表时间：
2021-05-13
影响因子：
4.6
通讯作者：
Ali S
中科院分区：
文献类型：
--
作者：
Abidi SH;Almansour NM;Amerzhanov D;Allemailem KS;Rafaqat W;Ibrahim MAA;la Fleur P;Lukac M;Ali S
随着严重急性呼吸道综合征冠状病毒2型（SARS-CoV-2）大流行席卷全球数百万人，对该病毒疫苗或药物的探索仍在继续。SARS-CoV-2的解旋酶蛋白代表了药物发现的有吸引力的靶点，因为抑制解旋酶活性可以抑制病毒复制。使用计算机模拟的方法，我们已经确定了药物与SARS-CoV-2解旋酶相互作用的基础上存在的氨基酸排列匹配的结合位点的药物在以前注释的蛋白质结构。使用分子对接、分子动力学（MD）模拟和MD后分析进一步分析显示RMSD ≤ 3.0 μ g的药物。使用这些方法，我们发现了12种与SARS-CoV-2解旋酶氨基酸具有强相互作用的药物。使用最近可用的SARS-CoV-2解旋酶结构（PDB ID：5 RL 6）进行分析。基于MM-GBSA方法，在12种药物中，两种药物，即泊沙康唑和格拉佐匹韦，显示出最有利的结合能，分别为− 54.8和− 49.1 kcal/mol。此外，在所有人冠状病毒中发现的保守氨基酸中，分别有10/11和10/12被grazoprevir和posaconazole靶向。这些残基是关键的DEAD样解旋酶C和DEXXQc_Upf1样/DEAD样解旋酶结构域的一部分。泊沙康唑和格拉佐匹韦与保守氨基酸的强相互作用表明，这些药物可以有效地对抗SARS-CoV-2。由于氨基酸在人类冠状病毒中是保守的，因此病毒不太可能对这些药物产生耐药性突变。由于这些药物已经在使用，它们可能会立即重新用于SARS-CoV-2治疗。
As the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic engulfs millions worldwide, the quest for vaccines or drugs against the virus continues. The helicase protein of SARS-CoV-2 represents an attractive target for drug discovery since inhibition of helicase activity can suppress viral replication. Using in silico approaches, we have identified drugs that interact with SARS-CoV-2 helicase based on the presence of amino acid arrangements matching binding sites of drugs in previously annotated protein structures. The drugs exhibiting an RMSD of ≤ 3.0 Å were further analyzed using molecular docking, molecular dynamics (MD) simulation, and post-MD analyses. Using these approaches, we found 12 drugs that showed strong interactions with SARS-CoV-2 helicase amino acids. The analyses were performed using the recently available SARS-CoV-2 helicase structure (PDB ID: 5RL6). Based on the MM-GBSA approach, out of the 12 drugs, two drugs, namely posaconazole and grazoprevir, showed the most favorable binding energy, − 54.8 and − 49.1 kcal/mol, respectively. Furthermore, of the amino acids found conserved among all human coronaviruses, 10/11 and 10/12 were targeted by, respectively, grazoprevir and posaconazole. These residues are part of the crucial DEAD-like helicase C and DEXXQc_Upf1-like/ DEAD-like helicase domains. Strong interactions of posaconazole and grazoprevir with conserved amino acids indicate that the drugs can be potent against SARS-CoV-2. Since the amino acids are conserved among the human coronaviruses, the virus is unlikely to develop resistance mutations against these drugs. Since these drugs are already in use, they may be immediately repurposed for SARS-CoV-2 therapy.
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影响因子：
4.9
作者：
Betz, UAK;Fischer, R;Rübsamen-Waigmann, H
通讯作者：
Rübsamen-Waigmann, H
DOI：
10.1038/nrd1853
发表时间：
2005-10
期刊：
Nature reviews. Drug discovery
影响因子：
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作者：
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通讯作者：
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4.6
作者：
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通讯作者：
Kim, Dong-Eun
影响因子：
82.9
作者：
Crute, JJ;Grygon, CA;Cordingley, MG
通讯作者：
Cordingley, MG
影响因子：
8.6
作者：
O'Boyle NM;Banck M;James CA;Morley C;Vandermeersch T;Hutchison GR
通讯作者：
Hutchison GR