Discovery of potential multi-target-directed ligands by targeting host-specific SARS-CoV-2 structurally conserved main protease
Discovery of potential multi-target-directed ligands by targeting host-specific SARS-CoV-2 structurally conserved main protease
复制标题
DOI：
10.1080/07391102.2020.1760137
复制
发表时间：
2020-05-05
影响因子：
4.4
通讯作者：
Kulkarni, Mahesh J.
中科院分区：
文献类型：
--
作者：
Joshi, Rakesh S.;Jagdale, Shounak S.;Kulkarni, Mahesh J.
严重急性呼吸系统综合征冠状病毒2（SARS-CoV-2）感染导致了当前的COVID-19大流行。在世界范围内，这种疾病已经感染了超过250万人，死亡率从5%到10%不等。在控制SARS-CoV-2病毒感染的药物研发方面，有几项努力正在进行。主要蛋白酶（M-Pro）在病毒复制和成熟中起关键作用，因此可以作为主要药物靶标。为了了解M-Pro的结构进化，我们进行了系统发育和序列相似性网络分析，描述了冠状病毒科M-Pro在病毒宿主特异性的五个簇中的分歧。这种聚类与M-Pro结构的比较得到了证实。此外，已经观察到，尽管一些残基存在变异，但骨架和结合位点构象是保守的。这些属性可以被利用来重新利用针对SARS-CoV-2 M-Pro的可用病毒蛋白酶抑制剂。与此一致，我们对7100种分子进行了类似的筛选，包括阿育吠陀止咳药物中存在的活性成分，抗病毒植物化学物质和合成抗SARS-CoV-2 M-Pro的抗病毒药物作为主要靶标。我们鉴定了几种天然分子，如δ-葡萄糖苷、杨梅苷、台湾甘草酮A、lactucopicrin 15-草酸酯、nymphoprotein A、afzelin、biorobin、橙皮苷和叶绿霉素B，其与SARS-CoV-2 M-Pro强烈结合。有趣的是，这些分子也显示出与SARS-CoV-2感染的其他潜在靶点如病毒受体人血管紧张素转换酶2（hACE-2）和RNA依赖性RNA聚合酶（RdRp）的强结合。我们预期，我们的多靶点定向配体的鉴定方法将为抗SARS-CoV-2感染的药物发现提供新的途径。作者：Ramaswamy H. Sarma
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in the current COVID-19 pandemic. Worldwide this disease has infected over 2.5 million individuals with a mortality rate ranging from 5 to 10%. There are several efforts going on in the drug discovery to control the SARS-CoV-2 viral infection. The main protease (M-Pro) plays a critical role in viral replication and maturation, thus can serve as the primary drug target. To understand the structural evolution of M-Pro, we have performed phylogenetic and Sequence Similarity Network analysis, that depicted divergence of Coronaviridae M-Pro in five clusters specific to viral hosts. This clustering was corroborated with the comparison of M-Pro structures. Furthermore, it has been observed that backbone and binding site conformations are conserved despite variation in some of the residues. These attributes can be exploited to repurpose available viral protease inhibitors against SARS-CoV-2 M-Pro. In agreement with this, we performed screening of similar to 7100 molecules including active ingredients present in the Ayurvedic anti-tussive medicines, anti-viral phytochemicals and synthetic anti-virals against SARS-CoV-2 M-Pro as the primary target. We identified several natural molecules like delta-viniferin, myricitrin, taiwanhomoflavone A, lactucopicrin 15-oxalate, nympholide A, afzelin, biorobin, hesperidin and phyllaemblicin B that strongly binds to SARS-CoV-2 M-Pro. Intrestingly, these molecules also showed strong binding with other potential targets of SARS-CoV-2 infection like viral receptor human angiotensin-converting enzyme 2 (hACE-2) and RNA dependent RNA polymerase (RdRp). We anticipate that our approach for identification of multi-target-directed ligand will provide new avenues for drug discovery against SARS-CoV-2 infection. Communicated by Ramaswamy H. Sarma