Theoretical Insights into the Anti-SARS-CoV-2 Activity of Chloroquine and Its Analogs and In Silico Screening of Main Protease Inhibitors
Theoretical Insights into the Anti-SARS-CoV-2 Activity of Chloroquine and Its Analogs and In Silico Screening of Main Protease Inhibitors
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DOI：
10.1021/acs.jproteome.0c00683
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发表时间：
2020-11-06
影响因子：
4.4
通讯作者：
Suchitra, Surendran
中科院分区：
文献类型：
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作者：
Achutha, A. S.;Pushpa, V. L.;Suchitra, Surendran
冠状病毒病(新冠肺炎)是当今世界范围内迅速蔓延的一种危险疾病。目前还没有治疗它的选择。药物再利用研究探索了抗疟疾药物氯喹和羟氯喹对SARS-CoV-2病毒的效力。这些药物可以抑制病毒蛋白水解酶，又称类糜蛋白酶半胱氨酸蛋白酶，也称为主酶(3CL(Pro))；因此，我们研究了氯喹的4-氨基喹啉和8-氨基喹啉类似物的结合效率。有6种化合物比氯喹和羟氯喹提供了更好的结合能。这些化合物与活性中心残基的相互作用，特别是与参与蛋白质降解的催化二聚体的Cys145和His41的相互作用，使这些化合物成为主要的蛋白水解酶抑制剂。建立了氯喹类似物结合能与分子参数的回归模型，R-2=0.9039，Q(2)=0.8848。该模型被用于从Asinex化合物库中筛选伯喹和分子的新类似物。对接和回归分析表明，这些类似物对3CLP(Pro)的抑制作用强于羟氯喹和伯氨喹。对HITS进行了分子动力学模拟，以确定其结合稳定性。最后，我们提出了四个与SARS-CoV-2具有药物相似性的化合物，这些化合物可以通过体外和体内研究进一步验证。
Corona virus disease (COVID-19) is a dangerous disease rapidly spreading all over the world today. Currently there are no treatment options for it. Drug repurposing studies explored the potency of antimalarial drugs, chloroquine and hydroxychloroquine, against SARS-CoV-2 virus. These drugs can inhibit the viral protease, called chymotrypsin-like cysteine protease, also known as Main protease (3CL(Pro)); hence, we studied the binding efficiencies of 4-aminoquinoline and 8-aminoquinoline analogs of chloroquine. Six compounds furnished better binding energies than chloroquine and hydroxychloroquine. The interactions with the active site residues especially with Cys145 and His41, which are involved in catalytic diad for proteolysis, make these compounds potent main protease inhibitors. A regression model correlating binding energy and the molecular descriptors for chloroquine analogs was generated with R-2 = 0.9039 and Q(2) = 0.8848. This model was used to screen new analogs of primaquine and molecules from the Asinex compound library. The docking and regression analysis showed these analogs to be more potent inhibitors of 3CLP(Pro) than hydroxychloroquine and primaquine. The molecular dynamic simulations of the hits were carried out to determine the binding stabilities. Finally, we propose four compounds that show drug likeness toward SARS-CoV-2 that can be further validated through in vitro and in vivo studies.