Identification of repurposing therapeutics toward SARS-CoV-2 main protease by virtual screening

SARS-CoV-2 causes the current global pandemic coronavirus disease 2019. Widely-available effective drugs could be a critical factor in halting the pandemic. The main protease (3CL(pro)) plays a vital role in viral replication; therefore, it is of great interest to find inhibitors for this enzyme. We applied the combination of virtual screening based on molecular docking derived from the crystal structure of the peptidomimetic inhibitors (N3, 13b, and 11a), and experimental verification revealed FDA-approved drugs that could inhibit the 3CL(pro) of SARS-CoV-2. Three drugs were selected using the binding energy criteria and subsequently performed the 3CL(pro) inhibition by enzyme-based assay. In addition, six common drugs were also chosen to study the 3CL(pro) inhibition. Among these compounds, lapatinib showed high efficiency of 3CL(pro) inhibition (IC50 value of 35 +/- 1 mu M and K-i of 23 +/- 1 mu M). The binding behavior of lapatinib against 3CL(pro) was elucidated by molecular dynamics simulations. This drug could well bind with 3CL(pro) residues in the five subsites S1', S1, S2, S3, and S4. Moreover, lapatinib's key chemical pharmacophore features toward SAR-CoV-2 3CL(pro) shared important HBD and HBA with potent peptidomimetic inhibitors. The rational design of lapatinib was subsequently carried out using the obtained results. Our discovery provides an effective repurposed drug and its newly designed analogs to inhibit SARS-CoV-2 3CL(pro).