The Potential of Usnic-Acid-Based Thiazolo-Thiophenes as Inhibitors of the Main Protease of SARS-CoV-2 Viruses
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemistry
2.1.1. The General Procedure for the Synthesis of Compounds 5a–g
2.1.2. The General Procedure for the Synthesis of Compounds 3a–g
2.2. Biological Experiments
2.2.1. Enzyme Inhibition Experiments
2.2.2. Evaluation of the Antiviral Activities against SARS-CoV-2 Viruses
2.3. Molecular Modeling
2.3.1. Protein and Ligand Preparation
2.3.2. Analysis of a Potential Binding Site
2.3.3. The Molecular Docking Procedure
2.3.4. Molecular Dynamics Simulations
3. Results and Discussion
3.1. Synthesis of Usnic Acid Derivatives
3.2. Enzymatic Inhibition Assays with SARS-CoV-2 3CLpro
3.3. Determination of the Kinetic Parameters of the Antiprotease Activity
3.4. Molecular Modeling
3.4.1. Molecular Docking
3.4.2. Analysis of Molecular Dynamics Simulations
3.5. Biological Testing for an Infectious Virus
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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comp | IC50, µM | comp | IC50, µM | ||
(+)-3a | 50.95 ± 6.33 | (−)-3a | 41.64 ± 4.97 | ||
(+)-3b | 49.65 ± 6.12 | (−)-3b | 40.42 ± 5.65 | ||
(+)-3c | 34.05 ± 4.45 | (−)-3c | 48.02 ± 6.21 | ||
(+)-3d | 40.67 ± 5.11 | (−)-3d | 41.01 ± 5.89 | ||
(+)-3e | 28.21 ± 1.41 | (−)-3e | 85.84 ± 10.15 | ||
(+)-3f | 50.22 ± 6.75 | (−)-3f | 72.77 ± 9.55 | ||
(+)-3g | >200 | (−)-3g | >200 | ||
(+)-1 | ̶ | >200 | (−)-1 | ̶ | >200 |
ML188 | ̶ | 1.56 ± 0.55 | Disulfiram | ̶ | 6.25 ± 1.97 |
GC376 | ̶ | 0.023 ± 0.004 | Ebselen | ̶ | 1.72 ± 0.4 |
Sample | IC50, µM | Km, µM (a) | Vmax, nM/s (b) | kcat, (s−1) (c) | kcat/Km (µM−1 s−1) (d) |
---|---|---|---|---|---|
3CLpro | - | 12.58 ± 1.99 | 1008.92 ± 96.15 | 3.36 ± 0.32 | 0.28 ± 0.05 |
(+)-3e | 28.21 ± 1.41 | 7.40 ± 1.34 | 334.26 ± 39.08 | 1.11 ± 0.13 | 0.15 ± 0.01 |
Ligand | Docking Parameters, kcal/mol (see Section 2.3.3) | |||
---|---|---|---|---|
Docking Score | LE | Emodel | IFD Score | |
(−)-3f | −14.403 | −0.400 | −118.365 | −670.92 |
(−)-3a | −13.805 | −0.394 | −108.414 | −668.88 |
(+)-3c | −13.336 | −0.370 | −142.033 | −668.19 |
(−)-3b | −12.594 | −0.360 | −110.742 | −667.56 |
(+)-3a | −12.089 | −0.345 | −117.862 | −667.42 |
(−)-3d | −10.899 | −0.303 | −109.117 | −665.55 |
(−)-3c | −10.739 | −0.298 | −111.977 | −665.54 |
(−)-3e | −10.277 | −0.285 | −92.602 | −665.06 |
(+)-3b | −10.689 | −0.305 | −93.545 | −665.02 |
(+)-3e | −9.372 | −0.260 | −99.295 | −664.68 |
(+)-3f | −8.376 | −0.233 | −85.940 | −663.75 |
(−)-3g | −9.237 | −0.243 | −85.007 | −663.54 |
(+)-1 | −9.566 | −0.383 | −78.894 | −662.44 |
(−)-1 | −9.464 | −0.379 | −60.914 | −661.46 |
(+)-3d | −7.295 | −0.203 | −74.813 | −660.77 |
(+)-3g | −7.723 | −0.203 | −87.327 | −660.67 |
ID Complex | IC50 (3CLPRO), µM | ΔGbind, kcal/mol | Interaction with Amino Acids | ||
---|---|---|---|---|---|
HB | π-π Stacking | Others | |||
3CLPRO–(+)-3e | 28.21 ± 1.41 | −66.22 | Ser46 Met49 Gly143 | His41 | none |
3CLPRO–(+)-3g | >200 | −55.99 | Gly143 Gly166 | His41 | none |
3CLPRO–(+)-1 | >200 | −36.63 | Asp187 | His41 | Asp187–clash |
Wuhan (a) | Delta (b) | Om. B.1. (c) | Om. 5.2 (d) | Om. XBB (e) | Om. BQ (f) | ||
---|---|---|---|---|---|---|---|
CC50 (g) | EC50 (h) (SI) (i) | EC50 (SI) | EC50 (SI) | EC50 (SI) | EC50 (SI) | EC50 (SI) | |
(+)-3e | 349.65 ± 21.2 | 25.3 ± 2.2 (14) | 41.5 ± 3.1 (8) | 20.7 ± 1.6 (17) | 20.01 ± 1.6 (17) | 22.4 ± 2.0 (15) | 32.25 ± 2.6 (11) |
Remdesivir | 710.9 ± 21.2 | 3.8 ± 0.42 (186) | 2.1 ± 0.16 (338) | 2.0 ± 0.13 (356) | 4.45 ± 1.0 (159) | 2.65 ± 0.6 (267) | 3.13 ± 0.9 (226) |
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Yarovaya, O.I.; Filimonov, A.S.; Baev, D.S.; Borisevich, S.S.; Zaykovskaya, A.V.; Chirkova, V.Y.; Marenina, M.K.; Meshkova, Y.V.; Belenkaya, S.V.; Shcherbakov, D.N.; et al. The Potential of Usnic-Acid-Based Thiazolo-Thiophenes as Inhibitors of the Main Protease of SARS-CoV-2 Viruses. Viruses 2024, 16, 215. https://doi.org/10.3390/v16020215
Yarovaya OI, Filimonov AS, Baev DS, Borisevich SS, Zaykovskaya AV, Chirkova VY, Marenina MK, Meshkova YV, Belenkaya SV, Shcherbakov DN, et al. The Potential of Usnic-Acid-Based Thiazolo-Thiophenes as Inhibitors of the Main Protease of SARS-CoV-2 Viruses. Viruses. 2024; 16(2):215. https://doi.org/10.3390/v16020215
Chicago/Turabian StyleYarovaya, Olga I., Aleksandr S. Filimonov, Dmitriy S. Baev, Sophia S. Borisevich, Anna V. Zaykovskaya, Varvara Yu. Chirkova, Mariya K. Marenina, Yulia V. Meshkova, Svetlana V. Belenkaya, Dmitriy N. Shcherbakov, and et al. 2024. "The Potential of Usnic-Acid-Based Thiazolo-Thiophenes as Inhibitors of the Main Protease of SARS-CoV-2 Viruses" Viruses 16, no. 2: 215. https://doi.org/10.3390/v16020215
APA StyleYarovaya, O. I., Filimonov, A. S., Baev, D. S., Borisevich, S. S., Zaykovskaya, A. V., Chirkova, V. Y., Marenina, M. K., Meshkova, Y. V., Belenkaya, S. V., Shcherbakov, D. N., Gureev, M. A., Luzina, O. A., Pyankov, O. V., Salakhutdinov, N. F., & Khvostov, M. V. (2024). The Potential of Usnic-Acid-Based Thiazolo-Thiophenes as Inhibitors of the Main Protease of SARS-CoV-2 Viruses. Viruses, 16(2), 215. https://doi.org/10.3390/v16020215