Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents
Vicky Mody, Joanna Ho, Savannah Wills, Ahmed Mawri, Latasha Lawson, Maximilian C C J C Ebert, Guillaume M Fortin, Srujana Rayalam, Shashidharamurthy Taval
Communications Biology, doi:10.1038/s42003-020-01577-x
Emerging outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is a major threat to public health. The morbidity is increasing due to lack of SARS-CoV-2 specific drugs. Herein, we have identified potential drugs that target the 3chymotrypsin like protease (3CLpro), the main protease that is pivotal for the replication of SARS-CoV-2. Computational molecular modeling was used to screen 3987 FDA approved drugs, and 47 drugs were selected to study their inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme in vitro. Our results indicate that boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin exhibited inhibitory effect towards 3CLpro enzymatic activity. The 100 ns molecular dynamics simulation studies showed that ivermectin may require homodimeric form of 3CLpro enzyme for its inhibitory activity. In summary, these molecules could be useful to develop highly specific therapeutically viable drugs to inhibit the SARS-CoV-2 replication either alone or in combination with drugs specific for other SARS-CoV-2 viral targets.
Supplementary Data 1 provides the data set for Figs. 2-5 , and Supplementary Figure 2 and 3 . Supplementary Data 2 and 3 provides data set for 3CLpro-OTDs docking study and Supplementary Data 4 for PIs and VNIs (S score for Table 1 and structural analysis for Fig. 6 ). Supplementary Data 5 provides data set for MD simulation study of 3CLPro homodimer with ivermectin, Supplementary Data 6 for 3CLPro monomer with ivermectin and Supplementary Data 7 for 3CLPro monomer with micafungin (Fig. 7 ). Supplementary Data 5-7 provides data set for Supplementary Fig. 3 (S score comparison from MD simulation study). Any remaining information can be obtained from the corresponding author upon reasonable request.
Author contributions V.M. and S.T. designed, performed and wrote the manuscript, S.R. performed the experiment and proofread the manuscript. M.E. performed MD simulation studies. G.M.F. helped with molecular docking studies. J.H., S.W., A.M., and L.L. collected the data on drugs. All authors reviewed the manuscript.
Competing interests The authors declare no competing interests.
Additional information Supplementary information is available for this paper at https://doi.org/10.1038/s42003-020-01577-x. Correspondence and requests for materials should be addressed to S.T. Reprints and permission information is available at http://www.nature.com/reprints Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and..
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