Role of Monovalent Ions in the NKCC1 Inhibition Mechanism Revealed through Molecular Simulations
Abstract
:1. Introduction
2. Results
2.1. Bumetanide Binding Pose Refinement
2.2. Bumetanide Binding to Human NKCC1
2.3. Binding Mode of Other Loop Diuretic Drugs
2.3.1. Azosemide Binding Mode
2.3.2. Furosemide Binding Mode
2.3.3. Ethacrynic Acid Binding Mode
3. Discussion
4. Materials and Methods
4.1. Binding Site Location and Docking
4.2. Model Building
4.3. Molecular Dynamics Simulation Details
4.4. Metadynamics Simulation Details
4.5. MM/PBSA Binding Free Energy Calculations and Alanine Scanning Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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ΔHb [kcal/mol] | −TΔS [kcal/mol] | ΔGb [kcal/mol] | |
---|---|---|---|
Bumetanide zNKCC1 | −27.8 ± 3.1 | 6.1 ± 2.3 | −21.7 ± 3.9 |
Bumetanide hNKCC1 | −32.6 ± 3.4 | 6.2 ± 3.3 | −26.4 ± 4.7 |
Azosemide | −27.6 ± 3.3 | 7.0 ± 3.2 | −20.6 ± 4.6 |
Furosemide | −24.8 ± 4.3 | 7.9 ± 4.0 | −16.9 ± 5.9 |
Ethacrynic acid | −22.1 ± 3.6 | 9.0 ± 3.4 | −13.1 ± 5.0 |
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Janoš, P.; Magistrato, A. Role of Monovalent Ions in the NKCC1 Inhibition Mechanism Revealed through Molecular Simulations. Int. J. Mol. Sci. 2022, 23, 15439. https://doi.org/10.3390/ijms232315439
Janoš P, Magistrato A. Role of Monovalent Ions in the NKCC1 Inhibition Mechanism Revealed through Molecular Simulations. International Journal of Molecular Sciences. 2022; 23(23):15439. https://doi.org/10.3390/ijms232315439
Chicago/Turabian StyleJanoš, Pavel, and Alessandra Magistrato. 2022. "Role of Monovalent Ions in the NKCC1 Inhibition Mechanism Revealed through Molecular Simulations" International Journal of Molecular Sciences 23, no. 23: 15439. https://doi.org/10.3390/ijms232315439