Toward the Identification of Potential α-Ketoamide Covalent Inhibitors for SARS-CoV-2 Main Protease: Fragment-Based Drug Design and MM-PBSA Calculations
Abstract
:1. Introduction
2. Results
2.1. Fragment-Based Drug Design (FBDD)
2.2. Covalent Docking
2.3. In Silico ADME and Toxicity Calculations
2.4. Molecular Dynamics (MD) Simulations
2.4.1. RMSD and RMSF Analysis
2.4.2. Evaluating the Stability of RMH148–Mpro
2.5. MM–PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) Binding Free Energy Calculations
3. Material and Methods
3.1. Fragment-Based Drug Design (FBDD)
3.2. Covalent Docking
3.3. In Silico ADME and Toxicity Calculations
3.4. Molecular Dynamics (MD)
3.5. MM-PBSA Calculation
4. Future Prospects for RMH148
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Hydrogen Bond Name | Average Distance (A0) ± SD |
---|---|
Hydrogen bond with Tyrosine54 | 3.17 ± 0.06 |
Hydrogen bond with Glutamic166 | 3.05 ± 0.12 |
Hydrogen bond with Glutamic166 | 3.05 ± 0.08 |
Hydrogen bond with Glutamic166 | 3.21 ± 0.1 |
Hydrogen bond with Glutamic166 | 3.31 ± 0.12 |
Hydrogen bond with Phenylalanine 140 | 2.98 ± 0.07 |
Hydrogen bond with Serine 144 | 3.17 ± 0.11 |
Hydrogen bond with Serine 144 | 3.18 ± 0.09 |
Hydrogen bond with Glycine 143 | 3.25 ± 0.15 |
Hydrogen bond with Glycine 143 | 3.29 ± 0.13 |
Hydrogen bond with Threonine 26 | 2.43 ± 0.04 |
Hydrogen bond with Threonine 26 | 2.58 ± 0.17 |
Hydrogen bond with Histidine 41 | 3.02 ± 0.14 |
Hydrogen bond with Histidine 164 | 3.00 ± 0.16 |
Hydrogen bond with Cysteine 145 | 2.71 ± 0.07 |
Complex | ΔE binding (kj/mol) | ΔE Electrostatic (kj/mol) | ΔE Van der Waals’ (kj/mol) | ΔE polar solvation (kj/mol) | SASA (kJ/mol) |
---|---|---|---|---|---|
RMH148–Mpro | −420 ± 21 | −149 ± 18 | −365 ± 26 | 131 ± 18 | −37 ± 2 |
O6K–Mpro | −388 ± 20 | −138 ± 19 | −333 ± 23 | 117 ± 16 | −34 ± 2 |
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Hassab, M.A.E.; Fares, M.; Amin, M.K.A.-H.; Al-Rashood, S.T.; Alharbi, A.; Eskandrani, R.O.; Alkahtani, H.M.; Eldehna, W.M. Toward the Identification of Potential α-Ketoamide Covalent Inhibitors for SARS-CoV-2 Main Protease: Fragment-Based Drug Design and MM-PBSA Calculations. Processes 2021, 9, 1004. https://doi.org/10.3390/pr9061004
Hassab MAE, Fares M, Amin MKA-H, Al-Rashood ST, Alharbi A, Eskandrani RO, Alkahtani HM, Eldehna WM. Toward the Identification of Potential α-Ketoamide Covalent Inhibitors for SARS-CoV-2 Main Protease: Fragment-Based Drug Design and MM-PBSA Calculations. Processes. 2021; 9(6):1004. https://doi.org/10.3390/pr9061004
Chicago/Turabian StyleHassab, Mahmoud A. El, Mohamed Fares, Mohammed K. Abdel-Hamid Amin, Sara T. Al-Rashood, Amal Alharbi, Razan O. Eskandrani, Hamad M. Alkahtani, and Wagdy M. Eldehna. 2021. "Toward the Identification of Potential α-Ketoamide Covalent Inhibitors for SARS-CoV-2 Main Protease: Fragment-Based Drug Design and MM-PBSA Calculations" Processes 9, no. 6: 1004. https://doi.org/10.3390/pr9061004