Laboratório de Bioinformática e Química Computacional, Departamento de Ciências Biológicas, Universidade Estadual do Sudoeste da Bahia (UESB), Jequié, Bahia, 45205-490, Brazil.
Department of Computer Science, Virginia Commonwealth University, Richmond, VA, 23284, USA.
F1000Res. 2020 Jun 4;9. doi: 10.12688/f1000research.23829.2. eCollection 2020.
SARS-CoV-2 is the causal agent of the current coronavirus disease 2019 (COVID-19) pandemic. They are enveloped, positive-sense, single-stranded RNA viruses of the Coronaviridae family. Proteases of SARS-CoV-2 are necessary for viral replication, structural assembly, and pathogenicity. The approximately 33.8 kDa M protease of SARS-CoV-2 is a non-human homologue and is highly conserved among several coronaviruses, indicating that M could be a potential drug target for Coronaviruses. Herein, we performed computational ligand screening of four pharmacophores (OEW, remdesivir, hydroxychloroquine and N3) that are presumed to have positive effects against SARS-CoV-2 M protease (6LU7), and also screened 50,000 natural compounds from the ZINC Database dataset against this protease target. We found 40 pharmacophore-like structures of natural compounds from diverse chemical classes that exhibited better affinity of docking as compared to the known ligands. The 11 best selected ligands, namely ZINC1845382, ZINC1875405, ZINC2092396, ZINC2104424, ZINC44018332, ZINC2101723, ZINC2094526, ZINC2094304, ZINC2104482, ZINC3984030, and ZINC1531664, are mainly classified as beta-carboline, alkaloids, and polyflavonoids, and all displayed interactions with dyad CYS145 and HIS41 from the protease pocket in a similar way as other known ligands. Our results suggest that these 11 molecules could be effective against SARS-CoV-2 protease and may be subsequently tested and to develop novel drugs against this virus.
SARS-CoV-2 是当前冠状病毒病 2019（COVID-19）大流行的病原体。它们是包膜的、正链、单链 RNA 病毒，属于冠状病毒科。SARS-CoV-2 的蛋白酶对于病毒复制、结构组装和致病性都是必要的。SARS-CoV-2 的约 33.8 kDa M 蛋白酶是非人类同源物，在几种冠状病毒中高度保守，表明 M 可能是冠状病毒的潜在药物靶点。在此，我们对四个假定对 SARS-CoV-2 M 蛋白酶（6LU7）有积极作用的药效团（OEW、瑞德西韦、羟氯喹和 N3）进行了计算机配体筛选，并且还针对该蛋白酶靶标筛选了来自 ZINC 数据库数据集的 50000 种天然化合物。我们从不同化学类别的天然化合物中发现了 40 个药效团样结构，它们的对接亲和力比已知配体更好。从 11 个最佳选择的配体，即 ZINC1845382、ZINC1875405、ZINC2092396、ZINC2104424、ZINC44018332、ZINC2101723、ZINC2094526、ZINC2094304、ZINC2104482、ZINC3984030 和 ZINC1531664，主要分为β-咔啉、生物碱和多黄酮类，并且都以与其他已知配体相似的方式与蛋白酶口袋中的二联体 CYS145 和 HIS41 相互作用。我们的结果表明，这 11 种分子可能对 SARS-CoV-2 蛋白酶有效，并且可能随后进行测试和开发针对这种病毒的新药。
