Molecular and Structural Aspects of Clinically Relevant Mutations of SARS-CoV-2 RNA-Dependent RNA Polymerase in Remdesivir-Treated Patients
Abstract
:1. Introduction
2. Results
2.1. Patients’ Characteristics
2.2. RdRp Mutational Profiles and Response to Remdesivir
2.3. Molecular Modeling
2.3.1. Molecular Docking and Thermodynamics Analysis
2.3.2. Structural Effects on the Global Motions of the 3M2 and 5M Mutants
2.3.3. Representative Pharmacophore Models (RPM) of Remdesivir Extracted during MDs
3. Discussion
4. Materials and Methods
4.1. Study Population and Mutational Analysis of RdRp
4.2. Evaluation of the Impact of RdRp Mutations on the Response to Remdesivir
4.3. SARS-CoV-2 Polymerase Model Preparation
4.4. Preparation of the SARS-CoV-2 Polymerase Mutant Models
4.5. Molecular Docking and Thermodynamics Analysis
4.6. Molecular Dynamics Simulations (MDs)
4.7. Principal Component Analysis (PCA)
4.8. Pharmacophore Model Generation along the MDs
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Rdrp Model | G-Score | ΔGbind |
---|---|---|
WT | −8.63 | −122.70 |
1M | −8.74 | −34.50 |
2M | −8.58 | −119.05 |
3M1 | −8.72 | −129.41 |
3M2 | −8.81 | −84.78 |
4M | −8.44 | −125.56 |
5M | −8.76 | −96.74 |
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Gratteri, C.; Ambrosio, F.A.; Lupia, A.; Moraca, F.; Catalanotti, B.; Costa, G.; Bellocchi, M.; Carioti, L.; Salpini, R.; Ceccherini-Silberstein, F.; et al. Molecular and Structural Aspects of Clinically Relevant Mutations of SARS-CoV-2 RNA-Dependent RNA Polymerase in Remdesivir-Treated Patients. Pharmaceuticals 2023, 16, 1143. https://doi.org/10.3390/ph16081143
Gratteri C, Ambrosio FA, Lupia A, Moraca F, Catalanotti B, Costa G, Bellocchi M, Carioti L, Salpini R, Ceccherini-Silberstein F, et al. Molecular and Structural Aspects of Clinically Relevant Mutations of SARS-CoV-2 RNA-Dependent RNA Polymerase in Remdesivir-Treated Patients. Pharmaceuticals. 2023; 16(8):1143. https://doi.org/10.3390/ph16081143
Chicago/Turabian StyleGratteri, Carmen, Francesca Alessandra Ambrosio, Antonio Lupia, Federica Moraca, Bruno Catalanotti, Giosuè Costa, Maria Bellocchi, Luca Carioti, Romina Salpini, Francesca Ceccherini-Silberstein, and et al. 2023. "Molecular and Structural Aspects of Clinically Relevant Mutations of SARS-CoV-2 RNA-Dependent RNA Polymerase in Remdesivir-Treated Patients" Pharmaceuticals 16, no. 8: 1143. https://doi.org/10.3390/ph16081143
APA StyleGratteri, C., Ambrosio, F. A., Lupia, A., Moraca, F., Catalanotti, B., Costa, G., Bellocchi, M., Carioti, L., Salpini, R., Ceccherini-Silberstein, F., Frazia, S. L., Malagnino, V., Sarmati, L., Svicher, V., Bryant, S., Artese, A., & Alcaro, S. (2023). Molecular and Structural Aspects of Clinically Relevant Mutations of SARS-CoV-2 RNA-Dependent RNA Polymerase in Remdesivir-Treated Patients. Pharmaceuticals, 16(8), 1143. https://doi.org/10.3390/ph16081143