RT Journal Article
SR Electronic
T1 Structure-based drug design, virtual screening and high-throughput screening rapidly identify antiviral leads targeting COVID-19
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.02.26.964882
DO 10.1101/2020.02.26.964882
A1 Zhenming Jin
A1 Xiaoyu Du
A1 Yechun Xu
A1 Yongqiang Deng
A1 Meiqin Liu
A1 Yao Zhao
A1 Bing Zhang
A1 Xiaofeng Li
A1 Leike Zhang
A1 Yinkai Duan
A1 Jing Yu
A1 Lin Wang
A1 Kailin Yang
A1 Fengjiang Liu
A1 Tian You
A1 Xiaoce Liu
A1 Xiuna Yang
A1 Fang Bai
A1 Hong Liu
A1 Xiang Liu
A1 Luke W. Guddat
A1 Gengfu Xiao
A1 Chengfeng Qin
A1 Zhengli Shi
A1 Hualiang Jiang
A1 Zihe Rao
A1 Haitao Yang
YR 2020
UL http://biorxiv.org/content/early/2020/02/27/2020.02.26.964882.abstract
AB A coronavirus identified as 2019 novel coronavirus (COVID-19) is the etiological agent responsible for the 2019-2020 viral pneumonia outbreak that commenced in Wuhan1-4. Currently there is no targeted therapeutics and effective treatment options remain very limited. In order to rapidly discover lead compounds for clinical use, we initiated a program of combined structure-assisted drug design, virtual drug screening, and high-throughput screening to identify new drug leads that target the COVID-19 main protease (Mpro). Mpro is a key coronavirus enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for this virus5,6. Here, we identified a mechanism-based inhibitor, N3, by computer-aided drug design and subsequently determined the crystal structure of COVID-19 Mpro in complex with this compound. Next, through a combination of structure-based virtual and high-throughput screening, we assayed over 10,000 compounds including approved drugs, drug candidates in clinical trials, and other pharmacologically active compounds as inhibitors of Mpro. Seven of these inhibit Mpro with IC50 values ranging from 0.48 to 16.62 μM. Ebselen, thiadiazolidinone-8 (TDZD-8) and N3 also exhibited strong antiviral activity in cell-based assays. Our results demonstrate the efficacy of this screening strategy, and establishes a new paradigm for the rapid discovery of drug leads with clinical potential in response to new infectious diseases where no specific drugs or vaccines are available.