Computational Selectivity Assessment of Protease Inhibitors against SARS-CoV-2
Abstract
:1. Introduction
2. Results and Discussion
2.1. Sequence and Active Site Comparison
2.2. Hydration and Small-Molecule Hot-Spots
2.3. Protease Selectivity Assessed by Molecular Docking
2.4. Toxicity Profiling
2.5. Selectivity from Different Perspectives
3. Materials and Methods
3.1. Selection of Proteases
3.2. Similarity of Proteins and Active Sites
3.3. Cosolvent MD Simulations
3.4. Classical MD Simulations
3.5. Water Molecules Tracking, Hot-Spots Identification
3.6. Molecular Docking and Validation
3.7. MD and MM/GBSA Post-Processing
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Protein | Function | Anti-Target a | Consequence of Inhibition |
---|---|---|---|
SARS-CoV-2 Mpro | Viral replication | - | antiviral activity |
SARS-CoV Mpro | Viral replication | no | antiviral activity |
Caspase-3 | Apoptosis | yes | interference with development |
Factor Xa | Coagulation | no | prevention of coagulopathies |
Cathepsin G | Immune system | yes | interference with immune response |
UCHL1 | Protein degradation | yes | interference with development and homeostasis |
Prostasin | Sodium balance | yes | alters homeostasis |
Thrombin | Coagulation | no | prevention of coagulopathies |
Chymase | Vasoconstriction | yes | interference with blood pressure |
Protein | Catalytic | Global | AS RMSD | Site | Fold | Similarity |
---|---|---|---|---|---|---|
Residues | Identity a | (Å)b | Similarity c | Index d | ||
SARS-CoV Mpro | H41, C145 | 96.1% | 0.2 | 0.91 | / | 0.90 |
Caspase-3 | H121, C163 | 11.6% | 1.9 | 0.67 | / | −0.74 |
Factor Xa | H57, D102, S195 | 11.6 % | 1.8 | 0.71 | all- | −0.67 |
Cathepsin G | H59, D103, S196 | 14.5% | 1.8 | 0.61 | all- | −0.71 |
UCHL1 | C90, H161, D176 | 15.7% | 2.8 | 0.74 | / | −0.98 |
Prostasin | H85, D134, S154 | 13.1% | 1.6 | 0.69 | all- | 0.26 |
Thrombin | H57, D102, S195 | 12.5% | 1.8 | 0.74 | all- | 0.31 |
Chymase | H45, D89, S182 | 19.0% | 1.9 | 0.64 | all- | −0.49 |
Protein | Docking | Cosolvents | Hydration | Site Similarity a |
---|---|---|---|---|
SARS-CoV Mpro | ** | * | ** | *** |
Caspase-3 | none | none | none | * |
Factor Xa | ** | ** | * | * |
Cathepsin G | *** | * | none | * |
UCHL1 | *** | * | * | none |
Prostasin | ** | none | * | ** |
Thrombin | ** | none | * | ** |
Chymase | ** | * | * | * |
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Fischer, A.; Sellner, M.; Mitusińska, K.; Bzówka, M.; Lill, M.A.; Góra, A.; Smieško, M. Computational Selectivity Assessment of Protease Inhibitors against SARS-CoV-2. Int. J. Mol. Sci. 2021, 22, 2065. https://doi.org/10.3390/ijms22042065
Fischer A, Sellner M, Mitusińska K, Bzówka M, Lill MA, Góra A, Smieško M. Computational Selectivity Assessment of Protease Inhibitors against SARS-CoV-2. International Journal of Molecular Sciences. 2021; 22(4):2065. https://doi.org/10.3390/ijms22042065
Chicago/Turabian StyleFischer, André, Manuel Sellner, Karolina Mitusińska, Maria Bzówka, Markus A. Lill, Artur Góra, and Martin Smieško. 2021. "Computational Selectivity Assessment of Protease Inhibitors against SARS-CoV-2" International Journal of Molecular Sciences 22, no. 4: 2065. https://doi.org/10.3390/ijms22042065