Binding Thermodynamics and Dissociation Kinetics Analysis Uncover the Key Structural Motifs of Phenoxyphenol Derivatives as the Direct InhA Inhibitors and the Hotspot Residues of InhA
Abstract
:1. Introduction
2. Results and Discussion
2.1. Van der Waals Interactions Are the Main Driving Force for the Binding of InhA Inhibitors
2.2. Critical Roles of Hotspot Residues and the Conformation of H6/H7 on the Binding of InhA Inhibitors
2.3. Pharmacophore Model Analysis Reveals the Structural Motifs of Phenoxyphenol Derivatives as InhA Direct Inhibitors
2.4. The Order of Residence Time Predicted by τRAMD Is Consistent with the Experiment
2.5. Steered MD Identifies the Intermediate States during the Dissociation Process
3. Materials and Methods
3.1. System Preparation
3.2. Classic Molecular Dynamics Simulations
3.3. Pharmacophore Modeling
3.4. Tau Random Acceleration Molecular Dynamics Simulation
3.5. Steered Molecular Dynamics Simulation
3.6. MM–GBSA Calculation
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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Energy | PT70 | PT91 | PT119 | PT501 | TCL | PT506 |
---|---|---|---|---|---|---|
ΔEele | −9.00 ± 0.09 | −17.01 ± 0.10 | −6.81 ± 0.11 | −11.72 ± 0.19 | −4.71 ± 0.08 | −7.56 ± 0.12 |
ΔEvdw | −39.18 ± 0.08 | −39.63 ± 0.07 | −40.74 ± 0.07 | −42.63 ± 0.08 | −34.01 ± 0.06 | −38.94 ± 0.07 |
ΔEMM | −48.18 ± 0.11 | −56.64 ± 0.11 | −47.55 ± 0.12 | −54.35 ± 0.19 | −38.72 ± 0.10 | −46.49 ± 0.16 |
ΔGSA | −5.58 ± 0.006 | −5.70 ± 0.006 | −5.82 ± 0.005 | −5.67 ± 0.007 | −4.38 ± 0.004 | −5.12 ± 0.007 |
ΔGGB | 20.91 ± 0.06 | 30.11 ± 0.09 | 21.09 ± 0.09 | 27.93 ± 0.15 | 14.77 ± 0.07 | 23.51 ± 0.10 |
ΔGsol | 15.34 ± 0.06 | 24.42 ± 0.08 | 15.27 ± 0.09 | 22.26 ± 0.15 | 10.38 ± 0.07 | 18.38 ± 0.10 |
ΔHbind | −32.84 ± 0.08 | −32.23 ± 0.07 | −32.27 ± 0.07 | −32.09 ± 0.08 | −28.34 ± 0.07 | −28.11 ± 0.09 |
Ki (nM) | 0.022 | 0.96 | 2.14 | 70 | 220 | 370 |
Pharmacophore | Phase Hypo Score | ROC | EF1% | AUC |
---|---|---|---|---|
AHRR_1 | 1.01 | 0.83 | 60.43 | 0.89 |
AHRR_3 | 0.93 | 0.67 | 60.43 | 0.77 |
HHRR_2 | 0.71 | 0.53 | 30.21 | 0.74 |
AHHRR_2 | 0.71 | 0.38 | 30.21 | 0.68 |
Ligand | Experiment (min) | τRAMD (ps) | Path |
---|---|---|---|
TCL | - | 33.9 | path1 or path2 |
PT91 | 20 | 91.4 | path1 |
PT70 | 24 | 177.4 | path1 |
PT119 | 80 | 386.5 | path2 |
PT501 | 190 | 518.9 | path1 |
PT506 | 194 | 2529.0 | path2 |
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Zhang, Q.; Han, J.; Zhu, Y.; Tan, S.; Liu, H. Binding Thermodynamics and Dissociation Kinetics Analysis Uncover the Key Structural Motifs of Phenoxyphenol Derivatives as the Direct InhA Inhibitors and the Hotspot Residues of InhA. Int. J. Mol. Sci. 2022, 23, 10102. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231710102
Zhang Q, Han J, Zhu Y, Tan S, Liu H. Binding Thermodynamics and Dissociation Kinetics Analysis Uncover the Key Structural Motifs of Phenoxyphenol Derivatives as the Direct InhA Inhibitors and the Hotspot Residues of InhA. International Journal of Molecular Sciences. 2022; 23(17):10102. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231710102
Chicago/Turabian StyleZhang, Qianqian, Jianting Han, Yongchang Zhu, Shuoyan Tan, and Huanxiang Liu. 2022. "Binding Thermodynamics and Dissociation Kinetics Analysis Uncover the Key Structural Motifs of Phenoxyphenol Derivatives as the Direct InhA Inhibitors and the Hotspot Residues of InhA" International Journal of Molecular Sciences 23, no. 17: 10102. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231710102