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

• Published in: Viruses Vol. 16; no. 6; p. 878
• Main Authors: Holmes, Jamie, Islam, Shahidul M., Milligan, Kimberly A.
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 30.05.2024; MDPI
• Subjects: Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Antiviral drugs; antiviral therapy; Cannabinoids; Cannabinoids - chemistry; Cannabinoids - pharmacology; Cannabis; cannabis compounds; Computer applications; Coronavirus Papain-Like Proteases - antagonists & inhibitors; Coronavirus Papain-Like Proteases - chemistry; Coronavirus Papain-Like Proteases - metabolism; Coronaviruses; COVID-19; COVID-19 Drug Treatment; COVID-19 infection; Cytokines; Health aspects; health services; Humans; immune evasion; Infections; Ligands; Marijuana; Medical innovations; molecular docking; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; molecular dynamics simulations; Mortality; Papain; PLpro; Protease Inhibitors - chemistry; Protease Inhibitors - metabolism; Protease Inhibitors - pharmacology; Proteases; Protein Binding; Proteinase inhibitors; proteinases; Proteins; Replication; SARS-CoV-2; SARS-CoV-2 - drug effects; SARS-CoV-2 - enzymology; Severe acute respiratory syndrome coronavirus 2; Simulation; therapeutics; Viral infections; virus replication; Virus Replication - drug effects; viruses; United States; computational methods; molecular dynamics simulations; viral replication; SARS-CoV-2; molecular docking; cannabis compounds; PLpro; antiviral therapy
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v16060878

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.