A Conserved Allosteric Site on Drug-Metabolizing CYPs: A Systematic Computational Assessment
Abstract
:1. Introduction
2. Results and Discussion
2.1. Simulation Techniques and Model Validation
2.2. Small Molecules Regularly Associate with the H1 Site of Several CYPs
2.3. The Effect of Allosteric Ligands Bound to the H1 Site Is Isoform-Dependent
3. Conclusions
4. Materials and Methods
4.1. Bioinformatics Analysis
4.2. Model Building
4.3. MD Simulations
4.4. Evaluation of the MD Trajectories
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Type | Membrane | Duration (ns) | Replicas a | LigOrtho b | LigAllo b |
---|---|---|---|---|---|
Cosolvent | no | 60 | 10 | no | no |
Association | no | 500 | 1 | no | yes c |
Equilibration | yes | 300 | 1 | yes | no |
Sampling | yes | 1005 | 3 | no | yes |
Metadynamics | yes | 50 | 10 | yes | no |
Metadynamics | yes | 50 | 10 | yes | yes |
Enzyme | Outcome T a | Outcome Pmax a | Significance | 2b | rB b 2c | 2f |
---|---|---|---|---|---|---|
CYP1A2 | H1 (0.386) | H1 (0.400) | no | = | + | = |
CYP2A6 | H1 (0.237) | H1 (0.179) | no | + | = | = |
CYP2B6 | H1 (0.204) | H1 (0.522) | no | + | n/a c | + |
CYP2C8 | H1 (0.010) | H1 (0.025) | yes | – | – | + |
CYP2C9 | WAT (0.675) | WAT (0.559) | no | = | – | + |
CYP2C19 | H1 (0.454) | H1 (0.862) | no | – | + | + |
CYP2D6 | H1 (0.001) | H1 (0.001) | yes | – | + | – |
CYP2E1 | WAT (0.232) | WAT (0.085) | yes | + | – | = |
CYP3A4 | H1 (0.571) | WAT (0.713) | no | n/a c | = | – |
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Fischer, A.; Smieško, M. A Conserved Allosteric Site on Drug-Metabolizing CYPs: A Systematic Computational Assessment. Int. J. Mol. Sci. 2021, 22, 13215. https://doi.org/10.3390/ijms222413215
Fischer A, Smieško M. A Conserved Allosteric Site on Drug-Metabolizing CYPs: A Systematic Computational Assessment. International Journal of Molecular Sciences. 2021; 22(24):13215. https://doi.org/10.3390/ijms222413215
Chicago/Turabian StyleFischer, André, and Martin Smieško. 2021. "A Conserved Allosteric Site on Drug-Metabolizing CYPs: A Systematic Computational Assessment" International Journal of Molecular Sciences 22, no. 24: 13215. https://doi.org/10.3390/ijms222413215