Exploring Cannabinoids as Potential Inhibitors of SARS-CoV-2 Papain-like Protease: Insights from Computational Analysis and Molecular Dynamics Simulations
Abstract
:1. Introduction
2. Materials and Methods
2.1. Retrieval and Preparation of Molecular Structures
2.1.1. Retrieval of Cannabinoids from PubChem
2.1.2. Retrieval of SARS-CoV-2 PLpro Protein Structure from Protein Data Bank (PDB)
2.2. Molecular Docking
2.2.1. Protein Structure Preparation Using AutoDock Tools
2.2.2. Ligand Pre-Processing
2.2.3. Grid-Based Docking Using AutoDock Vina
2.3. Binding Site Predictions and Interaction Analyses Using BIOVIA Discovery Studio
2.4. Evaluation Criteria for Docking Results
2.5. Validation and Verification Techniques
2.6. Molecular Dynamic Simulation
3. Results
3.1. Physicochemical Analysis of PLpro and Chemical Compounds
3.2. Computational Docking of Cannabinoids with SARS-CoV-2 PLpro
3.3. Binding Affinity and Interaction Patterns of Cannabinoids
3.3.1. Cannabigerolic Acid (CBGA)
3.3.2. Cannabidiolic Acid (CBDA)
3.3.3. Cannabigerol (CBG)
3.3.4. CBD
3.3.5. Cannabinoids with Other Targets
3.4. Significance of Docking Results and Implications for Therapeutic Development
3.4.1. Comparison with Existing Drug Candidates
3.4.2. Statistical Analysis and Data Presentation
3.5. MD Simulations of PLpro–Cannabinoid Compounds
3.5.1. Structure Stability Using Root Mean Square Deviation (RMSD)
- The overall structural stability of the protein fluctuates; however, it seems to have reached equilibrium towards the end of the simulation. The overall changes in the RMSD range between 5 Å to 8 Å, with fluctuations of 3 Å or less observed from 10 ns to 50 ns (backbone and side chains).
- The overall structural stability of the ligand does not undergo major fluctuations, indicating that the ligand has equilibrated (Lig fit lig).
- When bound to the protein, the RMSD of the ligand fluctuates in the initial stages but eventually reaches equilibrium. Given that the RMSD of the bound ligand is not significantly higher than that of the protein, it seems that, by the end of the simulations, the ligand is still bound in the initial binding pocket (Lig fit pot).
3.5.2. Root Mean Square Fluctuation (RMSF)
3.5.3. Protein Secondary Structure Analysis
3.5.4. Protein–Ligand Contacts throughout the Entire Simulation
3.5.5. Time Course of Interacting Residues and Ligands
3.5.6. Ligand Torsion Profile
4. Discussion
4.1. Interpretation of Docking Results in the Context of PLpro Inhibition
4.2. Implication of Understanding PLpro Inhibition Mechanisms
4.3. Comparison of Binding Affinities and Interaction Patterns among Cannabinoids
4.4. Potential Therapeutic Applications and Drug Development Strategies
4.5. Potential Mechanisms of Action of Cannabinoids on SARS-CoV-2 PLpro
4.6. Limitations of the Study and Future Directions
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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CBG | Cannabidiolic Acid | CBD | Cannabigerolic Acid | |
---|---|---|---|---|
MW (g/mol) | 173.17 | 358.5 | 511.79 | 360.5 |
HBD | 3 | 3 | 0 | 3 |
HBA | 5 | 4 | 4 | 4 |
RBs | 3 | 7 | 14 | 10 |
XLogP | −3.1 | 6.6 | 8.9 | 7.5 |
Heavy Atom | 12 | 26 | 37 | 26 |
TPSA (Å2) | 101 | 77.8 | 38.8 | 77.8 |
Molecular Structure | C21H32O2 | C22H30O4 | C21H30O2 | C22H32O4 |
Serial No. | Compound Name | Binding Affinity (kcal/Mol) | Interacting Residues | Type of Bonds |
---|---|---|---|---|
1 | Cannabidiolic acid (CBDA) | −5.3 | PRO248 | Pi–Alkyl: 2 Conventional Hydrogen Bond: 1 |
TYR264 | ||||
GLY266 | ||||
2 | Cannabigerolic acid (CBGA) | −6.1 | LYS105 | Alkyl and Pi–Alkyl: 8 |
TRP106 | ||||
TYR264 | ||||
TYR268 | ||||
ALA288 | ||||
LEU289 | ||||
3 | CBD | −5.0 | TYR268 | Alkyl: 3 Pi–Pi T-shaped: 1 |
ALA288 | ||||
LEU289 | ||||
4 | CBG | −4.6 | LYS105 | Alkyl: 3 Conventional Hydrogen Bond: 4 |
TRP106 | ||||
ASN267 | ||||
ALA288 | ||||
LEU289 |
Compounds | Binding Affinities (kcal/mol) | Interacting Residues | Type of Interactions | Van der Wall’s Interacting Residues |
---|---|---|---|---|
Cannabidiolic acid | −7.1 | VAL126, PHE192, LEU226, VAL227 | Pi–sigma, pi–pi T-shaped, alkyl, pi–alkyl | VAL120, ASN121, ARG102, GLY103, ILE119, TRP104, ILE128, HIS207, ILE203, ARG190 |
Cannabigerolic acid | −7.2 | VAL126, PHE192, LEU226, ILE101, TRP104, VAL227 | Pi–sigma, pi–pi T-shaped, alkyl (2), pi–alkyl (2) | ARG190, HIS207, PHE92, SER94, ARG102, ASN121, VAL120, VAL127, GLY103, ILE119, TYR170, ILE128, ILE203 |
CBD | −7 | ASN121, SER205, ARG190, VAL126, TRP104, LEU226 | H-bond (3), alkyl (2), pi–alkyl (2) | THR124, ASN125, ILE119, ILE203, VAL227, ILE128, PHE194, ILE101, GLU96, ARG102, HIS207 |
CBG | −5.4 | LYS300, SER297, ASP294, ASP290, ALA288, PHE59, VAL289 | H-bond (5), pi–alkyl, carbon hydrogen bond | PHE58, LEU296 |
Components | Cannabidiolic Acid (kcal/mol) | Cannabigerolic Acid (kcal/mol) | CBD (kcal/mol) | CBG (kcal/mol) |
---|---|---|---|---|
ΔGbind | −55.73 | −69.69 | −101.45 | −18.31 |
ΔGbind-Coulomb | −28.22 | −24.51 | 21.44 | −24.18 |
ΔGbind-Covalent | 9.42 | 5.27 | 7.37 | −0.70 |
ΔGbind-Hbond | −0.28 | −0.30 | −0.25 | −1.93 |
ΔGbind-Lipo | −44.26 | −52.89 | −68.59 | −9.70 |
ΔGbind-Packing | −0.31 | −0.42 | −0.10 | 0.00 |
ΔGbind-vdW | −39.05 | −41.19 | −55.13 | −18.51 |
ΔGbind-StrainEnergy | 9.06 | 17.29 | 15.57 | −1.05 |
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Holmes, J.; Islam, S.M.; Milligan, K.A. Exploring Cannabinoids as Potential Inhibitors of SARS-CoV-2 Papain-like Protease: Insights from Computational Analysis and Molecular Dynamics Simulations. Viruses 2024, 16, 878. https://doi.org/10.3390/v16060878
Holmes J, Islam SM, Milligan KA. Exploring Cannabinoids as Potential Inhibitors of SARS-CoV-2 Papain-like Protease: Insights from Computational Analysis and Molecular Dynamics Simulations. Viruses. 2024; 16(6):878. https://doi.org/10.3390/v16060878
Chicago/Turabian StyleHolmes, Jamie, Shahidul M. Islam, and Kimberly A. Milligan. 2024. "Exploring Cannabinoids as Potential Inhibitors of SARS-CoV-2 Papain-like Protease: Insights from Computational Analysis and Molecular Dynamics Simulations" Viruses 16, no. 6: 878. https://doi.org/10.3390/v16060878