A review of the latest research on Mpro targeting SARS-COV inhibitors

Abstract

Since the outbreak of COVID-19, the pandemic caused by SARS-CoV-2 infection is still spreading at an alarming rate and has caused huge loss of life and economic damage worldwide. Although more than one year has passed, effective treatments for COVID-19 and other pathogenic coronaviruses have not yet been developed. Therefore, the development of SARS-CoV-2 inhibitors is an urgent priority. Given that the M^pro sequences of SARS-CoV-2 and SARS-CoV-1 are 100% identical in the catalytic domain for protein cleavage, the viral main protease (M^pro) is one of the most extensive drug targets in all the drug targets being investigated for SARS-CoV-2. To provide scientific researchers with timely anti-SARS-CoV drug development information for M^pro, we focus on the past and current drug design and development strategies for M^Pro in this review. We believe that this review will provide meaningful guidance for the design and development of innovative drugs against COVID-19 and other pathogenic coronaviruses in the future.

Fig. 1. A, Chemical structures of compounds 1 and 2. B, X-ray crystal structure of compound 2 (thick stick with magenta carbon) with SARS-CoV-1 M^pro. Hydrogen bonds between the inhibitor and SARS-CoV-1 M^pro are shown as green dotted lines.

Fig. 2. A, Chemical structure of TG-0205221. B, Stereo-view of SARS-CoV-1 M^pro bound with the TG-0205221 inhibitor shown by electrostatic potential.

Fig. 3. A, Chemical structure of compound 3. B, Molecular dynamics simulated pose of compound 3 (green stick) bound to SARS-CoV-1 M^pro (PDB 1WOF, with red and cyan ribbons with molecular surfaces).

Fig. 4. A, Chemical structures of compounds 4 and 5. B, Molecular docking pose and binding interactions of compounds 4 and 5 (orange sticks) bound to SARS-CoV-1 M^pro (PDB ID: 1WOF). Only the residues (yellow color), which are engaged in binding to the ligands (orange sticks), are highlighted. Dotted black lines represent the hydrogen bonding interaction.

Fig. 5. Chemical structures of compounds 6–9.

Fig. 6. A, Chemical structures of compounds 10–15. B, GOLD docked conformation of 15 (green), covalently linked to Cys-145 of M^pro based on the 2V6N M^pro structure.

Fig. 7. A, Chemical structures of compounds GRL-0820 and GRL-0920. B, Molecular models of interactions of GRL-0920 with SARS-CoV-2 M^pro.

Fig. 8. Chemical structures of boceprevir, GC-376, calpain inhibitors II and XII.

Fig. 9. A, Chemical structures of compounds 16 and 17. B, Compound 17 in the substrate-binding cleft located between domains I and II of SARS-CoV-2 M^pro in the monoclinic crystal form (space group C2).

Fig. 10. A, Chemical structures of compounds 18 and 19. B, Schematic diagrams of SARS-CoV-2 M^pro–18 and SARS-CoV-2 M^pro–19 interactions.

Fig. 11. A, Chemical structures of danoprevir and lopinavir. B, Danoprevir and lopinavir docked in the binding site of SARS-CoV-2 M^pro.

Fig. 12. Chemical structures of the N3 inhibitor, ebselen, disulfiram, tideglusib, carmofur, shikonin, and PX-12.

Fig. 13. Chemical structures of Walrycin B, LLL-12 and Z-FA-FMK.

Fig. 14. A, Chemical structures of baicalin and baicalein. B, Interactions formed between baicalein (green) and surrounding residues (cyan). Residues as well as the ligand are shown as sticks and hydrogen bonds are represented by black-dashed lines.

Fig. 15. Chemical structures of MI-09 and MI-30.

Fig. 16. Chemical structures of GRL-1720, 20 and PF-00835231.

Fig. 17. A, Chemical structures of atazanavir, ceftaroline fosamil and telaprevir. B, The binding of drugs at subsites S1, S1′, S2, and S3 of SARS-CoV-2 M^pro. Ceftaroline fosamil and telaprevir are shown in stick forms in green and orange, respectively.

Fig. 18. A, Chemical structure of nelfinavir. B, Interactions between nelfinavir and associated residues in the homology model of SARS-CoV-2 M^pro. The data in red are the interaction distances (Å).

Fig. 19. Chemical structure of Z LVG CHN2.