Drug similarity and structure-based screening of medicinal compounds to target macrodomain-I from SARS-CoV-2 to rescue the host immune system: a molecular dynamics study
Drug similarity and structure-based screening of medicinal compounds to target macrodomain-I from SARS-CoV-2 to rescue the host immune system: a molecular dynamics study
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DOI：
10.1080/07391102.2020.1815583
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发表时间：
2020-09-04
影响因子：
4.4
通讯作者：
Ali, Syed Shujait
中科院分区：
文献类型：
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作者：
Babar, Zainib;Khan, Mazhar;Ali, Syed Shujait
最近在中国武汉首次发现的冠状病毒（SARS-CoV-2）的爆发，导致严重的肺炎感染，对公共卫生构成重大风险。在世界各地，研究人员正在不断尝试通过靶向不同的药物靶点来识别小分子抑制剂或候选疫苗。SARS-CoV-2宏域I有助于病毒复制和劫持宿主免疫系统，也是一个潜在的药物靶点。因此，本研究通过使用药物相似性、虚拟筛选、对接和再对接方法来靶向病毒大结构域-I。共筛选了64，043种化合物，并基于对接评分和与关键残基的相互作用鉴定了潜在的命中物。对前六个命中进行分子动力学模拟和自由能计算，并且每个重复三次。单残基能量分解分析表明，这些化合物与关键活性位点残基Asp 22、Ala 38、Asn 40、Val 44、Phe 144、Gly 46、Gly 47、Leu 127、Ser 128、Gly 130、Ile 131、Phe 132和Ala 155有显著的相互作用。在这里，我们还使用ADPr作为阳性对照来比较我们的结果。我们的研究结果表明，我们通过使用这样一个复杂的计算管道识别的命中可以通过靶向macrodomain-1来抑制SARS-CoV-2。我们强烈建议对这些化合物进行实验测试，它们可以拯救宿主免疫系统，并有助于遏制SARS-CoV-2引起的疾病。作者：Ramaswamy H. Sarma
The outbreak of the recent coronavirus (SARS-CoV-2), which causes a severe pneumonia infection, first identified in Wuhan, China, imposes significant risks to public health. Around the world, researchers are continuously trying to identify small molecule inhibitors or vaccine candidates by targeting different drug targets. The SARs-CoV-2 macrodomain-I, which helps in viral replication and hijacking the host immune system, is also a potential drug target. Hence, this study targeted viral macrodomain-I by using drug similarity, virtual screening, docking and re-docking approaches. A total of 64,043 compounds were screened, and potential hits were identified based on the docking score and interactions with the key residues. The top six hits were subjected to molecular dynamics simulation and Free energy calculations and repeated three times each. The per-residue energy decomposition analysis reported that these compounds significantly interact with Asp22, Ala38, Asn40, Val44, Phe144, Gly46, Gly47, Leu127, Ser128, Gly130, Ile131, Phe132 and Ala155 which are the critical active site residues. Here, we also used ADPr as a positive control to compare our results. Our results suggest that our identified hits by using such a complicated computational pipeline could inhibit the SARs-CoV-2 by targeting the macrodomain-1. We strongly recommend the experimental testing of these compounds, which could rescue the host immune system and could help to contain the disease caused by SARs-CoV-2. Communicated by Ramaswamy H. Sarma