Targeting the Ubiquinol-Reduction (Qi) Site of the Mitochondrial Cytochrome bc1 Complex for the Development of Next Generation Quinolone Antimalarials
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Cytochrome bc1 Purification
2.2. Crystallization, Data Collection, and Structure Refinement
2.3. Parasite Culture and Drug Sensitivity Measurements
2.4. Characterisation of Compounds and Their Purity
2.5. Plasmodium Falciparum Homology Model Generation
2.6. Molecular Docking
2.7. Bovine Cytochrome bc1 Activity Assay
3. Results
3.1. Inhibitory Effect of 4(1H)-Quinolones Binding to the Qi Site of Bovine Cytochrome bc1
3.2. Binding of 4(1H)-Quinolones to the Qi Site of Bovine Cytochrome bc1
3.3. Predicted Binding Mode of 4(1H)-Quinolones within the Plasmodium Falciparum Qi Site
3.4. Suggestions for Future Development of 4(1H)-Quinolones
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Compound | IC50 (nM) (3D7) | IC50 (nM) (TM90C2B) | IC50 (nM) (PfNDH2) | IC50 (nM) (Pfbc1) * | Bovine Cytochrome bc1 Inhibition (%) | |
---|---|---|---|---|---|---|
at 0.1 µM | at 1 µM | |||||
ELQ300 | 2.2 | 1.7 | NA | 0.56 | 22 ± 5 | 51 ± 7 |
GSK932121 | 6 | 6 † | >10,000 * | 7 | 65 ± 4 | 82 ± 5 |
GW844520 | 5 | 2 † | >10,000 * | 2 | 59 ± 6 | 79 ± 3 |
SCR0911 | 12 ± 3 | 7.2 | >1000 * | 80% inhibition at 100 nM * | 9 ± 2 | 72 ± 5 |
CK-2-67 | 117 ± 27 | 122 ± 26 | 16 | 38 | 90 ± 3 | 95 ± 1 |
RKA066 | 22 ± 0.4 | 217 ± 18 | 55 | 28 | 81 ± 4 | 93 ± 2 |
WDH-1U-4 | 36 ± 6 | 5 ± 2 | 492 | <10 | 7 ± 1 | 61 ± 3 |
bc1-CK-2-67 | bc1-RKA066 | bc1-WDH-1U-4 | |
---|---|---|---|
Data collection | |||
Space group | P6522 | P6522 | P6522 |
Cell dimensions | |||
a, b, c (Å) | 209.59, 209.59, 342.42 | 210.74, 210.74, 343.94 | 209.56, 209.56, 343.36 |
α, β, γ(°) | 90, 90, 120 | 90, 90, 120 | 90, 90, 120 |
Resolution (Å) | 49.81–3.20 (3.27–3.20) | 89.85–3.50 (3.60–3.50) | 90.74–3.50 (3.60–3.50) |
Rmerge | 0.21 (1.63) | 0.27 (1.42) | 0.20 (0.87) |
Rpim | 0.09 (0.69) | 0.09 (0.49) | 0.09 (0.40) |
CC1/2 | 0.997(0.357) | 0.987(0.450) | 0.968(0.543) |
I/σ | 8.5 (1.7) | 5.0 (1.3) | 7.0 (1.8) |
Completeness (%) | 95.7 (97.2) | 100 (100) | 97.4 (98.7) |
Redundancy | 9.4 (8.8) | 9.0 (8.8) | 5.4 (5.5) |
Refinement | |||
Resolution (Å) | 49.86–3.20 | 89.85–3.50 | 90.74–3.50 |
No. reflections | 66,560 | 54,431 | 52,188 |
Rwork/Rfree(%) | 21.4/25.02 | 22.09/23.82 | 21.71/24.57 |
No. atoms | |||
Protein | 16,142 | 15,688 | 15,617 |
Inhibitor | 30 | 31 | 30 |
Other ligands | 570 | 565 | 558 |
Water | 41 | 8 | 36 |
B-factors (Å2) | |||
Protein | 90.68 | 140.24 | 133.88 |
Inhibitor | 110.02 | 83.02 | 142.60 |
Other ligands | 110.02 | 151.01 | 149.60 |
Water | 54.87 | 45.87 | 40.79 |
R.m.s. deviations | |||
Bond lengths (Å) | 0.007 | 0.009 | 0.008 |
Bond angles (°) | 1.681 | 1.505 | 1.437 |
Ramachandran Plot | |||
Preferred (%) | 96.02 | 95.98 | 96.17 |
Allowed (%) | 3.59 | 3.66 | 3.63 |
Outliers (%) | 0.39 | 0.35 | 0.20 |
PDB code | 7R3V | 6ZFU | 6ZFS |
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Amporndanai, K.; Pinthong, N.; O’Neill, P.M.; Hong, W.D.; Amewu, R.K.; Pidathala, C.; Berry, N.G.; Leung, S.C.; Ward, S.A.; Biagini, G.A.; et al. Targeting the Ubiquinol-Reduction (Qi) Site of the Mitochondrial Cytochrome bc1 Complex for the Development of Next Generation Quinolone Antimalarials. Biology 2022, 11, 1109. https://doi.org/10.3390/biology11081109
Amporndanai K, Pinthong N, O’Neill PM, Hong WD, Amewu RK, Pidathala C, Berry NG, Leung SC, Ward SA, Biagini GA, et al. Targeting the Ubiquinol-Reduction (Qi) Site of the Mitochondrial Cytochrome bc1 Complex for the Development of Next Generation Quinolone Antimalarials. Biology. 2022; 11(8):1109. https://doi.org/10.3390/biology11081109
Chicago/Turabian StyleAmporndanai, Kangsa, Nattapon Pinthong, Paul M. O’Neill, W. David Hong, Richard K. Amewu, Chandrakala Pidathala, Neil G. Berry, Suet C. Leung, Stephen A. Ward, Giancarlo A. Biagini, and et al. 2022. "Targeting the Ubiquinol-Reduction (Qi) Site of the Mitochondrial Cytochrome bc1 Complex for the Development of Next Generation Quinolone Antimalarials" Biology 11, no. 8: 1109. https://doi.org/10.3390/biology11081109