Rational Approach toward COVID-19’s Main Protease Inhibitors: A Hierarchical Biochemoinformatics Analysis
Abstract
:1. Introduction
2. Results and Discussion
2.1. Prediction of Pharmacokinetic Properties
2.2. Toxicity Risk Analysis
2.3. Biological Target Prediction
2.4. Molecular Docking Study
2.5. Structural Dissimilarity Study Using the Tanimoto Index
2.6. Molecular Dynamics (MD) Simulations
3. Materials and Methods
3.1. Selection of Compounds
3.2. Pharmacokinetic Properties Prediction
3.3. Toxicological Properties Prediction
3.4. Biological Target Prediction
3.5. Molecular Docking Study
3.6. Structural Dissimilarity Study Using the Tanimoto Index
3.7. Molecular Dynamics (MD) Simulation on SARS-CoV-2 Mpro
3.8. MMPBSA Calculations
3.9. Hydrogen Bond Capacity Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Structure | HIA [a] | PCaco2 [a] | PSkin [a] | PPB [a] | BBB [b] | CNS [b] |
---|---|---|---|---|---|---|
1 | 60.287 | 20.933 | −2.638 | 77.409 | −2.277 | −3.520 |
2 | 63.552 | 20.925 | −2.566 | 81.291 | −2.343 | −3.619 |
3 | 66.583 | 20.925 | −2.509 | 83.779 | −2.231 | −3.592 |
4 | 63.540 | 20.913 | −2.579 | 79.224 | −2.267 | −3.533 |
5 | 67.464 | 20.912 | −2.471 | 78.844 | −2.295 | −3.669 |
6 | 63.552 | 20.925 | −2.566 | 81.291 | −2.343 | −3.619 |
7 | 66.583 | 20.925 | −2.509 | 83.779 | −2.231 | −3.592 |
8 | 40.555 | 20.837 | −2.585 | 68.971 | −2.338 | −3.898 |
9 | 66.583 | 20.796 | −2.528 | 81.117 | −2.264 | −3.625 |
10 | 66.573 | 20.933 | −2.510 | 83.616 | −2.388 | −3.529 |
11 | 51.168 | 14.396 | −2.413 | 78.180 | −1.521 | −3.677 |
12 | 54.588 | 20.776 | −2.527 | 83.263 | −2.262 | −3.643 |
13 | 69.365 | 20.964 | −2.473 | 84.498 | −2.297 | −3.521 |
14 | 79.926 | 20.032 | −2.501 | 82.428 | −2.517 | −3.593 |
15 | 60.302 | 19.484 | −2.659 | 69.612 | −2.224 | −3.751 |
16 | 57.071 | 20.988 | −2.938 | 66.840 | −2.257 | −3.921 |
17 | 56.760 | 21.004 | −2.606 | 66.391 | −2.293 | −3.854 |
18 | 94.928 | 23.600 | −2.942 | 100.000 | −0.053 | −2.051 |
19 | 96.829 | 22.372 | −3.657 | 89.676 | 0.211 | −1.943 |
20 | 97.181 | 23.469 | −4.150 | 95.434 | −1.262 | −2.336 |
21 | 96.937 | 21.930 | −4.167 | 96.221 | −1.265 | −2.446 |
22 | 94.143 | 41.601 | −2.137 | 92.115 | −0.205 | −2.529 |
FJC | 85.571 | 19.359 | −4.323 | 90.905 | −0.992 | −3.347 |
Lopinavir | 93.802 | 24.605 | −2.520 | 89.712 | −0.830 | −2.935 |
Ritonavir | 93.192 | 35.883 | −2.617 | 86.385 | −1.665 | −3.295 |
Structure | Carcino [a] | Ames [a] | Hepato [a] | MTD [b] | hERG I [b] | hERG II [b] |
---|---|---|---|---|---|---|
1 | - | - | Yes | 0.731 | No | No |
2 | - | - | Yes | 0.695 | No | No |
3 | - | - | No | 0.672 | No | No |
4 | - | - | Yes | 0.645 | No | No |
5 | - | - | Yes | 0.737 | No | No |
6 | - | - | Yes | 0.695 | No | No |
7 | - | - | No | 0.672 | No | No |
8 | - | - | Yes | 0.741 | No | No |
9 | - | - | Yes | 0.659 | No | No |
10 | - | - | Yes | 0.697 | No | No |
11 | - | - | No | 0.637 | No | No |
12 | - | - | Yes | 0.665 | No | No |
13 | - | - | Yes | 0.775 | No | No |
14 | - | - | Yes | 0.698 | No | No |
15 | - | - | Yes | 0.660 | No | No |
16 | - | - | Yes | 0.666 | No | No |
17 | - | - | Yes | 0.656 | No | No |
18 | - | + | Yes | −0.614 | No | Yes |
19 | - | - | Yes | −0.091 | No | No |
20 | - | + | Yes | 0.795 | No | Yes |
21 | - | - | Yes | 0.777 | No | Yes |
22 | - | + | No | 0.320 | No | Yes |
FJC | - | - | Yes | 0.426 | No | Yes |
Lopinavir | - | - | Yes | −0.297 | No | Yes |
Ritonavir | - | - | Yes | 0.096 | No | Yes |
Structure | Affinity Binding to Proteases [a] (%) | Protease Inhibitor [b] |
---|---|---|
1 | 20.0 | 0.04 |
2 | 13.3 | −0.06 |
3 | 20.0 | −0.27 |
4 | 33.3 | −0.04 |
5 | 6.7 | −0.07 |
6 | 13.3 | −0.06 |
7 | 20.0 | −0.27 |
8 | 26.7 | −0.13 |
9 | 20.0 | −0.20 |
10 | 40.0 | −0.20 |
11 | 46.7 | −0.86 |
12 | 20.0 | −0.30 |
13 | 13.3 | −0.34 |
14 | 20.0 | −0.10 |
15 | 26.7 | −0.02 |
16 | 20.0 | 0.24 |
17 | 18.0 | 0.14 |
18 | 8.0 | 0.18 |
19 | 20.0 | −0.06 |
20 | 6.7 | −0.42 |
21 | 6.7 | −0.58 |
22 | 13.3 | 0.16 |
FJC | 26.7 | 0.70 |
Lopinavir | 26.7 | 0.42 |
Ritonavir | 20.0 | 0.35 |
Ligand | Binding Energy (kcal/mol) | 2D Interactions of Residues |
---|---|---|
1 | −7.70 | |
10 | −8.40 | |
12 | −7.90 | |
15 | −7.70 | |
19 | −6.90 | |
21 | −7.80 | |
FJC | −8.20 | |
Lopinavir | −6.90 | |
Ritonavir | −7.20 |
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Bastos, R.S.; de Aguiar, C.P.O.; Cruz, J.N.; Ramos, R.S.; Kimani, N.M.; de Souza, J.S.N.; Chaves, M.H.; de Freitas, H.F.; Pita, S.S.R.; Santos, C.B.R.d. Rational Approach toward COVID-19’s Main Protease Inhibitors: A Hierarchical Biochemoinformatics Analysis. Int. J. Mol. Sci. 2024, 25, 6715. https://doi.org/10.3390/ijms25126715
Bastos RS, de Aguiar CPO, Cruz JN, Ramos RS, Kimani NM, de Souza JSN, Chaves MH, de Freitas HF, Pita SSR, Santos CBRd. Rational Approach toward COVID-19’s Main Protease Inhibitors: A Hierarchical Biochemoinformatics Analysis. International Journal of Molecular Sciences. 2024; 25(12):6715. https://doi.org/10.3390/ijms25126715
Chicago/Turabian StyleBastos, Ruan S., Christiane P. O. de Aguiar, Jorddy N. Cruz, Ryan S. Ramos, Njogu M. Kimani, João S. N. de Souza, Mariana H. Chaves, Humberto F. de Freitas, Samuel S. R. Pita, and Cleydson B. R. dos Santos. 2024. "Rational Approach toward COVID-19’s Main Protease Inhibitors: A Hierarchical Biochemoinformatics Analysis" International Journal of Molecular Sciences 25, no. 12: 6715. https://doi.org/10.3390/ijms25126715