Prediction of potential inhibitors of the dimeric SARS-CoV2 main proteinase through the MM/GBSA approach

Abstract

Since the emergence of SARS-CoV2, to date, no effective antiviral drug has been approved to treat the disease, and no vaccine against SARS-CoV2 is available. Under this scenario, the combination of two HIV-1 protease inhibitors, lopinavir and ritonavir, has attracted attention since they have been previously employed against the SARS-CoV main proteinase (M^pro) and exhibited some signs of effectiveness. Recently, the 3D structure of SARS-CoV2 M^pro was constructed based on the monomeric SARS-CoV M^pro and employed to identify potential approved small inhibitors against SARS-CoV2 M^pro, allowing the selection of 15 drugs among 1903 approved drugs to be employed. In this study, we performed docking of these 15 approved drugs against the recently solved X-ray crystallography structure of SARS-CoV2 M^pro in the monomeric and dimeric states; the latter is the functional state that was determined in a biological context, and these were submitted to molecular dynamics (MD) simulations coupled with the molecular mechanics generalized Born surface area (MM/GBSA) approach to obtain insight into the inhibitory activity of these compounds. Similar studies were performed with lopinavir and ritonavir coupled to monomeric and dimeric SARS-CoV M^pro and SARS-CoV2 M^pro to compare the inhibitory differences. Our study provides the structural and energetic basis of the inhibitory properties of lopinavir and ritonavir on SARS-CoV M^pro and SARS-CoV2 M^pro, allowing us to identify two FDA-approved drugs that can be used against SARS-CoV2 M^pro. This study also demonstrated that drug discovery requires the dimeric state to obtain good results.

Keywords: Docking; MD simulations; Proteinase; SARS-CoV; SARS-CoV2.

Graphical abstract

Scheme 1

2D structure of the compounds used in this research. A) indomethacin, B) naftazone, C) ofloxacin, D) zopiclone, E) lopinavir, F) sofosbuvir, G) pitavastatin, H) eszopiclone, I) ondansetron, J) perampanel, K) fenoterol, L) azelastine, M) ritonavir, N) celecoxib, O) nelfinavir, P) praziquantel, Q) lemborexant, R) Inhibitor N3, S) TG-0205221, T) niclosamide, and U) chloroquine.

Fig. 1

Binding conformation of complexes between ligands and monomeric SARS-CoV2 M^pro. Maps of the interaction of monomeric SARS-CoV2 M^pro with naftazone (A), zopiclone (B), sofosbuvir (C), pitavastatin (D), eszopiclone (E), and perampanel (F). Each complex corresponds to the most populated conformation obtained thorough MD simulation. The receptor is represented in a green cartoon representation, the interacting residues are depicted in green sticks, and the ligand is shown in a ball and stick representation. The figure was built with PyMOL [25]. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Binding conformation of complexes between ligands and monomeric SARS-CoV2 M^pro and SARS-CoV M^pro. Diagrams of the interaction of complexes of monomeric SARS-CoV2 M^pro with azelastine (A), celecoxib (B), ondansetron (C) and lemborexant (D) and lopinavir (E). Diagrams of the interaction of monomeric SARS-CoV M^pro with lopinavir (F) and ritonavir (G).

Fig. 3

Binding conformation of complexes of ligands with dimeric SARS-CoV2 M^pro. Indomethacin coupled to subunit 2 (A), naftazone bound to subunits 1 (B) and 2 (C), ofloxacin bound to subunit 1 (D), and zopiclone coupled to subunits 1 (E) and 2 (F) of dimeric SARS-CoV2 M^pro.

Fig. 4

Binding conformation of complexes of ligands with dimeric SARS-CoV2 M^pro. Sofosbuvir bound at subunits 1 (A) and 2 (B), pitavastatin bound at subunits 1 (C) and 2 (D), and eszopiclone bound at subunits 1 (E) and 2 (F) of dimeric SARS-CoV2 M^pro.

Fig. 5

Binding conformation of complexes of ligands with dimeric SARS-CoV2 M^pro. Perampanel bound at subunits 1 or 2 (A and B), fenoterol bound at subunits 1 or 2 (Fig. C and D), and azelastine bound at subunits 1 and 2 (Fig. E and F) of dimeric SARS-CoV2 M^pro.

Fig. 6

Binding conformation of complexes of ligands with dimeric SARS-CoV2 M^pro. Celecoxib bound at subunits 1 and 2 (A and B), nelfinavir bound at subunits 1 and 2 (Fig. 6C and D), and praziquantel bound at subunits 1 and 2 (Fig. 6E and F) of dimeric SARS-CoV2 M^pro.

Fig. 7

Binding conformation of complexes of ligands with dimeric SARS-CoV2 M^pro. Ondansetron bound at subunits 1 and 2 (A and B), lemborexant bound at subunit 2 (C), lopinavir at subunits 1 (D) and 2 (E) and ritonavir at subunit 1 (F) of dimeric SARS-CoV2 M^pro.

Fig. 8

Binding conformation of complexes of ligands with dimeric SARS-CoV2 and SARS-CoV M^pro. Ritonavir bound at subunit 2 (A) of dimeric SARS-CoV2 M^pro. Lopinavir coupled at subunits 1 (B) and 2 (C) and ritonavir at subunit 1 (D) of dimeric SARS-CoV M^pro.