FEP-based screening prompts drug repositioning against COVID-19

The new coronavirus COVID-19, also known as SARS-CoV-2, has infected more than 300,000 patients and become a global health emergency due to the very high risk of spread and impact of COVID-19. There are no specific drugs or vaccines against COVID-19, thus effective antiviral agents are still urgently needed to combat this virus. Herein, the FEP (free energy perturbation)-based screening strategy is newly derived as a rapid protocol to accurately reposition potential agents against COVID-19 by targeting viral proteinase Mpro. Restrain energy distribution (RED) function was derived to optimize the alchemical pathway of FEP, which greatly accelerated the calculations and first made FEP possible in the virtual screening of the FDA-approved drugs database. As a result, fifteen out of twenty-five drugs validated in vitro exhibited considerable inhibitory potencies towards Mpro. Among them, the most potent Mpro inhibitor dipyridamole potentially inhibited NF-kB signaling pathway and inflammatory responses, and has just finished the first round clinical trials. Our result demonstrated that the FEP-based screening showed remarkable advantages in prompting drug repositioning against COVID-19.