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. 2024 May 30;16(6):878.
doi: 10.3390/v16060878.

Exploring Cannabinoids as Potential Inhibitors of SARS-CoV-2 Papain-like Protease: Insights from Computational Analysis and Molecular Dynamics Simulations

Jamie Holmes  1 , Shahidul M Islam  1 , Kimberly A Milligan  1
Affiliations

Exploring Cannabinoids as Potential Inhibitors of SARS-CoV-2 Papain-like Protease: Insights from Computational Analysis and Molecular Dynamics Simulations

Jamie Holmes et al. Viruses. .

Abstract

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a global COVID-19 pandemic, challenging healthcare systems worldwide. Effective therapeutic strategies against this novel coronavirus remain limited, underscoring the urgent need for innovative approaches. The present research investigates the potential of cannabis compounds as therapeutic agents against SARS-CoV-2 through their interaction with the virus's papain-like protease (PLpro) protein, a crucial element in viral replication and immune evasion. Computational methods, including molecular docking and molecular dynamics (MD) simulations, were employed to screen cannabis compounds against PLpro and analyze their binding mechanisms and interaction patterns. The results showed cannabinoids with binding affinities ranging from -6.1 kcal/mol to -4.6 kcal/mol, forming interactions with PLpro. Notably, Cannabigerolic and Cannabidiolic acids exhibited strong binding contacts with critical residues in PLpro's active region, indicating their potential as viral replication inhibitors. MD simulations revealed the dynamic behavior of cannabinoid-PLpro complexes, highlighting stable binding conformations and conformational changes over time. These findings shed light on the mechanisms underlying cannabis interaction with SARS-CoV-2 PLpro, aiding in the rational design of antiviral therapies. Future research will focus on experimental validation, optimizing binding affinity and selectivity, and preclinical assessments to develop effective treatments against COVID-19.

Keywords: PLpro; SARS-CoV-2; antiviral therapy; cannabis compounds; computational methods; molecular docking; molecular dynamics simulations; viral replication.

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Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Molecular docking interaction of (a) CBDA, (b) CBGA, (c) CBD, and (d) CBG with SARS-CoV-2 PLpro protein. Ribbon diagram with the solvent surface rendered view and 2-dimensional interaction diagram showing interactions of respective cannabinoids with SARS-CoV-2, PLpro protein active site. The various interaction types are indicated by different colors provided in the color panel at the bottom. BIOVIA Discovery Studio 2020 client was used to visualize and analyze the interactions.
Figure 2
Figure 2
(A) Surface mapping of 6W9C-Cannabigerolic acid complex with forest green and hot pink colors respectively. (B) Showing 2D interaction view of Cannabigerolic acid with the SARS-CoV-2 PLpro receptor. The legend for the interactions involved is given in the left lower box. (C) Labeled interacting residues with Cannabigerolic acid and calculated distances. (D) Cannabigerolic acid (hot pink) and interacting residues (forest green) in stick representation, while receptor is in cartoon form with 50% transparency.
Figure 3
Figure 3
(A) Surface mapping of 6W9C-Cannabidiolic acid complex with forest green and red colors, respectively. (B) Showing 2D interaction view of Cannabidiolic acid with the SARS-CoV-2 PLpro receptor. The legend for the interactions involved is given in the left lower box. (C) Labeled interacting residues with Cannabidiolic acid and calculated distance. (D) Cannabidiolic acid (red color) and interacting residues (forest green) in stick representation, while receptor is in cartoon form with 50% transparency.
Figure 4
Figure 4
Cannabinoid superimposition with existing drug candidate.
Figure 5
Figure 5
Binding free energy calculations via MMGBSA analysis.
Figure 6
Figure 6
Protein and ligand RMSD plot.
Figure 7
Figure 7
Protein residues interacting with the ligand CBGA.
Figure 8
Figure 8
Protein residues interacting with the ligand molecule across the time course.
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