High-throughput Screening and Experimental Identification of Potent Drugs Targeting SARS-CoV-2 Main Protease
Yan Li, Jinyong Zhang, Ning Wang, Yanjing Zhang, Yongjun Yang, Yue Yuan, Haiming Jing, Xin Liu, Sisi Wu, Ping Luo, Weijun Zhang, Dongshui Lu, Hao Zeng, Gang Guo, Quanming Zou · 2020
Abstract The main protease (Mpro) is one of the best-characterized drug targets among coronaviruses. In the current study, we adopted a multiple cross-docking strategy against different crystal structures of SARS-CoV-2 Mpro to perform computer-based high-throughput virtual screening of possible inhibitors from a drug database using Autodock Vina and SeeSAR software, combined with our in-house automatic processing scripts. The KDs between screened candidates and Mpro were determined using Biacore. Seven drugs were found to fit the substrate-binding pocket of Mpro with a stable conformation, showing high KDs that ranged from 6.79E-7 M to 5.20E-5 M. Finally, mutagenesis studies confirmed that these drugs interact with Mpro specifically, suggesting that our method was reliable and convincing. Given the safety of these old drugs, they may serve as promising candidates to treat the infection of SARS-CoV-2. Our results also provide rational explanations for the behaviour of five drugs evaluated in clinical trials.