QSAR Modeling of SARS-CoV MproInhibitors Identifies Sufugolix, Cenicriviroc, Proglumetacin, and Other Drugs as Candidates for Repurposing against SARS-CoV-2
QSAR Modeling of SARS-CoV MproInhibitors Identifies Sufugolix, Cenicriviroc, Proglumetacin, and Other Drugs as Candidates for Repurposing against SARS-CoV-2
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DOI：
10.1002/minf.202000113
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发表时间：
2020-08-24
影响因子：
3.6
通讯作者：
Tropsha, Alexander
中科院分区：
文献类型：
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作者：
Alves, Vinicius M.;Bobrowski, Tesia;Tropsha, Alexander
SARS-CoV-2的主要蛋白酶（M-pro）已被提议作为COVID-19的主要药物靶标之一。我们已经确定了测试化合物对SARS-CoV的密切相关的M（pro）（96%序列同一性，100%活性位点保守性）的抑制活性的实验数据。我们开发了这些抑制剂的QSAR模型，并采用这些模型对DrugBank数据库中的所有药物进行虚拟筛选。平行探索相似性搜索和分子对接，但对接未能正确区分实验活性和非活性化合物，因此不依赖于前瞻性虚拟筛选。我们的模型确定了42种化合物作为共识计算命中。在我们的计算研究之后，NCATS报告了在SARS-CoV-2细胞病变效应试验中对其药物收集进行实验筛选的结果（https：//opendata.ncats.nih.gov/covid19/）。巧合的是，NCATS测试了我们42个命中中的11个，其中三个，赛尼克韦罗（AC（50）为8.9 μ M），丙谷美辛（独立测试两次，AC（50）为8.9 μ M和12.5 μ M）和舒夫戈利斯（AC（50）12.6 μ M），显示出活性。这些观察结果支持了我们的建模方法和模型的价值，用于指导推定的抗COVID-19候选药物的实验研究。本研究中使用的所有数据和模型均可通过补充材料、GitHub（https：//github.com/alvesvm/sars-cov-mpro）和Chembench门户网站（https：//chembench.mml.unc.edu/）公开获取。
The main protease (M-pro) of the SARS-CoV-2 has been proposed as one of the major drug targets for COVID-19. We have identified the experimental data on the inhibitory activity of compounds tested against the closely related (96 % sequence identity, 100 % active site conservation) M(pro)of SARS-CoV. We developed QSAR models of these inhibitors and employed these models for virtual screening of all drugs in the DrugBank database. Similarity searching and molecular docking were explored in parallel, but docking failed to correctly discriminate between experimentally active and inactive compounds, so it was not relied upon for prospective virtual screening. Forty-two compounds were identified by our models as consensus computational hits. Subsequent to our computational studies, NCATS reported the results of experimental screening of their drug collection in SARS-CoV-2 cytopathic effect assay (https://opendata.ncats.nih.gov/covid19/). Coincidentally, NCATS tested 11 of our 42 hits, and three of them, cenicriviroc (AC(50)of 8.9 mu M), proglumetacin (tested twice independently, with AC(50)of 8.9 mu M and 12.5 mu M), and sufugolix (AC(50)12.6 mu M), were shown to be active. These observations support the value of our modeling approaches and models for guiding the experimental investigations of putative anti-COVID-19 drug candidates. All data and models used in this study are publicly available via Supplementary Materials, GitHub (https://github.com/alvesvm/sars-cov-mpro), and Chembench web portal (https://chembench.mml.unc.edu/).