A large-scale computational screen identifies strong potential inhibitors for disrupting SARS-CoV-2 S-protein and human ACE2 interaction.

SARS-CoV-2 has infected millions of individuals across the globe and has killed over 2.7 million people. Even though vaccines against this virus have recently been introduced, the antibody generated in the process has been reported to decline quickly. This can reduce the efficacy of vaccines over time and can result in re-infections. Thus, drugs that are effective against COVID-19 can provide a second line of defence and can prevent occurrence of the severe form of the disease. The interaction between SARS-CoV2 S-protein and human ACE2 (hACE2) is essential for the infection of the virus. Thus, drugs that block this interaction could potentially inhibit SARS-CoV-2 infection into the host cells. To identify such drugs, we first analyzed the recently published crystal structure of S-protein-hACE2 complex and identified essential residues of both S-protein and hACE2 for this interaction. We used this knowledge to virtually dock a drug library containing 4115 drug molecules against S-protein for repurposing drugs that could inhibit binding of S-protein to hACE2. We identified several potential inhibitors based on their docking scores, pharmacological effects and ability to block residues of S protein required for interaction with hACE2. The top inhibitors included drugs used for the treatment of hepatitis C (velpatasvir, pibrentasvir) as well as several vitamin D derivatives. Several molecules obtained from our screen already have good experimental support in published literature. Thus, we believe that our results will facilitate the discovery of an effective drug against COVID-19. Communicated by Ramaswamy H. Sarma.