Molecular insights into the inhibition mechanism of harringtonine against essential proteins associated with SARS-CoV-2 entry.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently posed a serious threat to global public health. Harringtonine (HT), as a small-molecule antagonist, has antiviral activity against a variety of viruses. There is evidence that HT can inhibit the SARS-CoV-2 entry into host cells by blocking the Spike protein and transmembrane protease serine 2 (TMPRSS2). However, the molecular mechanism underlying the inhibition effect of HT is largely elusive. Here, docking and all-atom molecular dynamics simulations were used to investigate the mechanism of HT against the receptor binding domain (RBD) of Spike, TMPRSS2, as well as the complex of RBD and angiotensin-converting enzyme 2 complex (RBD-ACE2). The results reveal that HT binds to all proteins primarily through hydrogen bond and hydrophobic interactions. Binding with HT influences the structural stability and dynamic motility processes of each protein. The interactions of HT with residues N33, H34 and K353 of ACE2, and residue K417 and Y453 of RBD contribute to disrupting the binding affinity between RBD and ACE2, which may hinder the virus entry into host cells. Our research provides molecular insights into the inhibition mechanism of HT against SARS-CoV-2 associated proteins, which will help for the novel antiviral drugs development.