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. 2021 Aug;39(13):4936-4948.
doi: 10.1080/07391102.2020.1782768. Epub 2020 Jun 24.

Pharmacoinformatics and molecular dynamics simulation studies reveal potential covalent and FDA-approved inhibitors of SARS-CoV-2 main protease 3CLpro

Mubarak A Alamri  1 , Muhammad Tahir Ul Qamar  2 , Muhammad Usman Mirza  3 , Rajendra Bhadane  4   5 , Safar M Alqahtani  1 , Iqra Muneer  6 , Matheus Froeyen  3 , Outi M H Salo-Ahen  4   5
Affiliations

Pharmacoinformatics and molecular dynamics simulation studies reveal potential covalent and FDA-approved inhibitors of SARS-CoV-2 main protease 3CLpro

Mubarak A Alamri et al. J Biomol Struct Dyn. 2021 Aug.

Abstract

The SARS-CoV-2 was confirmed to cause the global pandemic of coronavirus disease 2019 (COVID-19). The 3-chymotrypsin-like protease (3CLpro), an essential enzyme for viral replication, is a valid target to combat SARS-CoV and MERS-CoV. In this work, we present a structure-based study to identify potential covalent inhibitors containing a variety of chemical warheads. The targeted Asinex Focused Covalent (AFCL) library was screened based on different reaction types and potential covalent inhibitors were identified. In addition, we screened FDA-approved protease inhibitors to find candidates to be repurposed against SARS-CoV-2 3CLpro. A number of compounds with significant covalent docking scores were identified. These compounds were able to establish a covalent bond (C-S) with the reactive thiol group of Cys145 and to form favorable interactions with residues lining the substrate-binding site. Moreover, paritaprevir and simeprevir from FDA-approved protease inhibitors were identified as potential inhibitors of SARS-CoV-2 3CLpro. The mechanism and dynamic stability of binding between the identified compounds and SARS-CoV-2 3CLpro were characterized by molecular dynamics (MD) simulations. The identified compounds are potential inhibitors worthy of further development as COVID-19 drugs. Importantly, the identified FDA-approved anti-hepatitis-C virus (HCV) drugs paritaprevir and simeprevir could be ready for clinical trials to treat infected patients and help curb COVID-19. Communicated by Ramaswamy H. Sarma.

Keywords: 3CL protease; COVID-19; SARS-CoV-2; covalent inhibitors; molecular dynamics simulation; paritaprevir; simeprevir.

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Figures

Figure 1.
Figure 1.
(A) Ribbon representation of the superimposed SARS-CoV-2 3CLpro (red) (PDB ID 6LU7) bound to inhibitor N3 (cyan sticks), SARS-CoV 3CLpro (yellow) bound to an aza-peptide epoxide inhibitor (green sticks) (PDB: 2A5I) and MERS-CoV 3CLpro (blue) bound to GC813 (magenta). (B) Zoom-in to the main protease active site. The catalytic dyad His41, Cys145 within SARS-CoV-2, SARS-CoV and MERS-CoV main proteases is shown in red, yellow, and blue sticks, respectively.
Figure 2.
Figure 2.
(A) Covalently re-docked N3 peptide (white carbons, ball and stick presentation) in the active site of the SARS-CoV-2 3CLpro (PDB ID 6LU7, grey surface presentation). The original crystal pose of the peptide is shown as ball and stick presentation with green carbon atoms. Atom color code: red – oxygen; blue – nitrogen. Hydrogen atoms are omitted for clarity. (B) Two stereoisomers of N3 peptide (see the chiral center at the carbon next to the reactive vinyl group). (C) RMSD of Cα atoms of the N3 peptide (re-docked N3 in black, co-crystalized N3 in red) over a period of 20 ns.
Figure 3.
Figure 3.
(A) Molecular surface representation of SARS-CoV-2 3CLpro with the covalently docked hit compounds. (B) Zoomed-in SARS-CoV-2 3CLpro substrate-binding pocket labelled with subsites S1, S2 and S4. (C–E) Representation of the chemical reaction of the reactive thiol group of Cys145 with the reactive nucleophilic group of the hit compounds, and the corresponding covalently docked poses (green sticks) inside the substrate-binding site of SARS-CoV-2 3CLpro (white ribbon presentation, ligand-interacting amino acids are shown in sticks). Atom color code: carbon – green/white; nitrogen – blue; oxygen – red; sulfur – yellow. Hydrogen atoms are omitted for clarity.
Figure 4.
Figure 4.
Molecular dynamics simulations of SARS-CoV-2 3CLpro. (A) RMSD and (B) RMSF of both unbound (apo) and ligand-bound SARS-CoV-2 3CLpro. The domains of SARS-CoV-2 3CLpro are displayed in (B).
Figure 5.
Figure 5.
3D binding mode and 2D molecular interactions of identified candidate compounds within the active site of SARS-CoV-2 3CLpro (PDB ID 6LU7); (A–B) paritaprevir; (C–D) simeprevir. The catalytic dyad His41, Cys145 within the active site is shown in orange sticks.
Figure 6.
Figure 6.
Molecular dynamics simulations of SARS-CoV-2 3CLpro. (A) RMSD and (B) RMSF of SARS-CoV-2 3CLpro with bound paritaprevir and simeprevir.
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