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. 2022 Apr;40(7):3170-3184.
doi: 10.1080/07391102.2020.1845976. Epub 2020 Nov 12.

Reprofiling of approved drugs against SARS-CoV-2 main protease: an in-silico study

Prateek Kumar  1 , Taniya Bhardwaj  1 , Ankur Kumar  1 , Bhuvaneshwari R Gehi  1 , Shivani K Kapuganti  1 , Neha Garg  2 , Gopal Nath  3 , Rajanish Giri  1
Affiliations

Reprofiling of approved drugs against SARS-CoV-2 main protease: an in-silico study

Prateek Kumar et al. J Biomol Struct Dyn. 2022 Apr.

Abstract

Given the COVID-19 pandemic, currently, there are many drugs in clinical trials against this virus. Among the excellent drug targets of SARS-CoV-2 are its proteases (Nsp3 and Nsp5) that plays vital role in polyprotein processing giving rise to functional nonstructural proteins, essential for viral replication and survival. Nsp5 (also known as Mpro) hydrolyzes replicase polyprotein (1ab) at eleven different sites. For targeting Mpro, we have employed drug repurposing approach to identify potential inhibitors of SARS-CoV-2 in a shorter time span. Screening of approved drugs through docking reveals Hyaluronic acid and Acarbose among the top hits which are showing strong interactions with catalytic site residues of Mpro. We have also performed docking of drugs Lopinavir, Ribavirin, and Azithromycin on SARS-CoV-2 Mpro. Further, binding of these compounds (Hyaluronic acid, Acarbose, and Lopinavir) is validated by extensive molecular dynamics simulation of 500 ns where these drugs show stable binding with Mpro. We believe that the high-affinity binding of these compounds will help in designing novel strategies for structure-based drug discovery against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

Keywords: COVID-19; Mpro; Nsp5; SARS-CoV-2; approved drug; protease.

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Conflict of interest statement

All authors declare that there is no financial or any other type of competing interest.

Figures

Figure 1.
Figure 1.
Predicted druggable sites of Mpro. Five druggable sites are represented with different colors – site 1: blue; site 2: purple; site 3: cyan; site 4: green and site 5: grey. Site 1 shows the highest site score and Dscore, and hence is selected for docking studies.
Figure 2.
Figure 2.
Molecular interaction of Hyaluronic Acid (HA) at Mpro active site 1. In surface and binding pose views, ligand is represented with orange color and interacting residues are labeled. In 2D interaction view, arrows correspond to H-bonds formed between HA and Mpro.
Figure 3.
Figure 3.
Molecular interaction of Acarbose with Mpro active site 1. In surface and binding pose views, ligand is represented with orange color and interacting residues are labeled. In 2D interaction view, arrows correspond to H-bonds formed between Acarbose and Mpro.
Figure 4.
Figure 4.
Molecular interaction of Amikacin with Mpro active site 1. In surface and binding pose views, ligand is represented with orange color and interacting residues are labeled. In 2D interaction view, arrows corresponds to H-bonds formed between Amikacin and Mpro.
Figure 5.
Figure 5.
2D Molecular interaction views of (a) Ribostamycin, (b) Octreotide and (c) Paromomycin with Mpro. Arrows correspond to H-bonds formed by the drug molecule with residues of Mpro.
Figure 6.
Figure 6.
2D Molecular interaction views of (a) Lopinavir, (b) Azithromycin and (c) Ribavirin with Mpro. Arrows, blue-red straight line and green straight line corresponds to H-bonds, salt bridge and pi-pi interactions formed between the drug molecules with residues of Mpro.
Figure 7.
Figure 7.
Evaluation of root mean square deviation (RMSD) from molecular dynamic trajectory of Mpro (6LU7) in complex with HA, Acarbose, Amikacin and Lopinavir.
Figure 8.
Figure 8.
Evaluation of root mean square fluctuation (RMSF) of Mpro (6LU7) residues upon binding with HA, Acarbose, Amikacin and Lopinavir.
Figure 9.
Figure 9.
Evaluation of protein structure compactness through radius of gyration (Rg) for HA, Acarbose, Amikacin and Lopinavir bound Mpro (6LU7).
Figure 10.
Figure 10.
Depiction of principal component analysis (PCA). Projection on eigenvector 1 against eigenvector 2 for HA, Acarbose, Amikacin and Lopinavir bound Mpro (6LU7).
Figure 11.
Figure 11.
Evaluation of solvent accessible surface area (SASA) of Mpro (6LU7) upon binding with HA, Acarbose, Amikacin and Lopinavir. Acarbose and HA bound Mpro have attained more stable states during simulation.
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