Molecular Docking Guided Grid-Independent Descriptor Analysis to Probe the Impact of Water Molecules on Conformational Changes of hERG Inhibitors in Drug Trapping Phenomenon
Abstract
:1. Introduction
2. Results
2.1. Molecular Docking Simulations
2.2. Grid-Independent Descriptor Analysis
2.3. External Test Set Validation
3. Discussion
4. Materials and Methods
4.1. Molecular Docking Simulations
4.1.1. Structure Preparation
4.1.2. Molecular Dynamic Simulations
4.1.3. Solvation of Binding Cavity
- c: represents the average gain/loss of rotational and translational entropy.
- α, β: are constants which were determined during training (along with c) and are forcefield-dependent. If not using an AMBER forcefield, the parameters will be set by default to the MMFF trained parameters.
- EcoulEcoul: is the coulombic electrostatic term which is calculated using currently loaded charges, using a constant dielectric of 1.
- EsolEsol: is the solvation electrostatic term which is calculated using the GB/VI solvation model. For more information on the GB/VI solvation model.
- Evdw: is the van der Waals contribution to the binding.
- SAweighted: is the surface area, weighted by exposure. This weighting scheme penalizes exposed surface area.
- External H-bond: protein–ligand hydrogen bond energy,
- External vdw: protein–ligand van der Waals (vdw) energy,
- Internal vdw: ligand internal vdw energy,
- Internal torsion: ligand torsional strain energy.
4.1.4. Final Pose Selection and Ligand–Protein Interaction Analysis
4.1.5. Protein–Ligand Interaction Fingerprints
4.2. Grid Independent Descriptors Model Development
Test Set Validation
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
hERG | Human ether a-go-go related gene |
aLQTS | acquired Long QT syndrome |
GRIND | GRId-Independent Descriptors |
QSAR | Quantitative Structure Activity Relationship |
MIFs | Molecular Interaction Fields |
PLIF | Protein Ligand Interaction Fingerprints |
TdPs | Torsade de Pointes |
ICH | International Conference on Harmonisation |
MD | Molecular Dynamics |
GB/VI | Generalized Born Solvation Model |
PLS | Partial Least Square |
LOO | Leave One Out |
SDEP | Standard Deviation of Error Prediction |
FFD | Fractional Factorial Design |
CLACC | Consistently Large Auto And Cross-Correlation |
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Compound | −ΔG of Docked Complexes (kcal/mol) | −ΔG of Docked Complexes (kcal/ mol) | ||
---|---|---|---|---|
Non-Solvated-Open | Solvated-Open | Non-Solvated-Closed | Solvated-Closed | |
MK-499 | −388 | −372 | −949 | −467 |
E4031 | −487 | −389 | −946 | −447 |
Dofetilide | −397 | −385 | −861 | −436 |
Trimethoprim | −363 | −296 | −736 | −338 |
hERG Channel Docked Conformatio-ns | Complete Variable GBVI/WSA Score | FFD 1ST Cycle GBVI/WSA Score | Test Set 1 Validation | Test Set 2 Validation | Complete Variable GoldScore | FFD 1ST Cycle GoldScore | Test Set 1 Validation | Test Set 2 Validation | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
LVa | q2 | r2 | SDEPb | LV | q2 | r2 | SDEP | R2 | R2 | LV | q2 | r2 | SDEP | LV | q2 | r2 | SDEP | R2 | R2 | |
Non-solvated -open | 1 | 0.43 | 0.55 | 0.10 | 2 | 0.54 | 0.62 | 0.98 | 0.58 | 0.51 | 3 | 0.35 | 0.47 | 1.14 | 2 | 0.43 | 0.52 | 1.07 | 0.48 | 0.41 |
Solvated -open | 2 | 0.42 | 0.53 | 1.07 | 2 | 0.44 | 0.55 | 1.05 | 0.52 | 0.41 | 2 | 0.34 | 0.47 | 1.14 | 2 | 0.36 | 0.49 | 1.12 | 0.32 | 0.31 |
Non-solvated-closed | 3 | 0.42 | 0.62 | 1.07 | 2 | 0.49 | 0.58 | 1.00 | 0.48 | 0.46 | 3 | 0.33 | 0.42 | 1.10 | 2 | 0.38 | 0.50 | 1.02 | 0.38 | 0.36 |
Solvated-closed | 1 | 0.41 | 0.51 | 1.07 | 2 | 0.43 | 0.53 | 1.05 | 0.36 | 0.38 | 2 | 0.31 | 0.38 | 1.12 | 2 | 0.36 | 0.48 | 1.07 | 0.31 | 0.28 |
Important Feature | Hotspots Indicating | Impact | Open (cryo_EM) Conformations Distance Å | Closed (Homology) Conformations Distance Å | ||
---|---|---|---|---|---|---|
Non-Solvated-Open | Solvated-Open | Non-Solvated-Closed | Solvated-Closed | |||
DRY-DRY | A particular Distance between two hydrophobic moieties | + | 12.0–12.4 | 12.4–12.8 | 10.0–10.4 | 10.8–11.2 |
DRY-TIP | A particular Distance between hydrophobic moiety and steric hot spot | + | 13.6–14.0 | 14.4–14.8 | 14.8–15.2 | 15.2–15.6 |
DRY-O | A particular Distance between hydrophobic moiety and hydrogen bond donor feature | + | 7.2–7.6 | 6.8–7.2 | 11.6–12.0 | 12.0–12.4 |
N1-N1 | A particular Distance between two hydrogen bond acceptor groups | - | 4.8–5.2 | 5.2–5.6 | 4.0–4.4 | 3.2–3.6 |
O-N1 | A particular Distance between hydrogen bond donor and hydrogen bond acceptor feature | - | 16.0–16.4 | 16.4–16.8 | 15.6–16.0 | 16.0–16.4 |
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Munawar, S.; Vandenberg, J.I.; Jabeen, I. Molecular Docking Guided Grid-Independent Descriptor Analysis to Probe the Impact of Water Molecules on Conformational Changes of hERG Inhibitors in Drug Trapping Phenomenon. Int. J. Mol. Sci. 2019, 20, 3385. https://doi.org/10.3390/ijms20143385
Munawar S, Vandenberg JI, Jabeen I. Molecular Docking Guided Grid-Independent Descriptor Analysis to Probe the Impact of Water Molecules on Conformational Changes of hERG Inhibitors in Drug Trapping Phenomenon. International Journal of Molecular Sciences. 2019; 20(14):3385. https://doi.org/10.3390/ijms20143385
Chicago/Turabian StyleMunawar, Saba, Jamie I. Vandenberg, and Ishrat Jabeen. 2019. "Molecular Docking Guided Grid-Independent Descriptor Analysis to Probe the Impact of Water Molecules on Conformational Changes of hERG Inhibitors in Drug Trapping Phenomenon" International Journal of Molecular Sciences 20, no. 14: 3385. https://doi.org/10.3390/ijms20143385