Identifying Novel ATX Inhibitors via Combinatory Virtual Screening Using Crystallography-Derived Pharmacophore Modelling, Docking Study, and QSAR Analysis
Abstract
:1. Introduction
2. Materials and Methods
2.1. Development of Pharmacophore Models and PB-VS
2.2. Molecular Docking Calculation
2.3. Development of 3D QSAR Model and QSARB-VS
3. Results and Discussion
3.1. Establishment of Pharmacophore Models
3.2. Validation of Pharmacophore Models
3.3. Determination of Parameters and Scoring Functions
3.4. Development of the 3D QSAR Model
3.5. Searching for New ATX Inhibitors
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Ethical Approval
References
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Sample Availability: Samples of the compounds are not available from the authors. |
Pharmacophore Abstract | |||
---|---|---|---|
Pharmacophore Models | Frequency of Properties | Feature Set | Selectivity Score |
5M7M 01 | 5 | A1H1H2H3R2 | 1.3840 |
5M7M 02 | 4 | A1H1H2R2 | 1.0423 |
5M7M 03 | 4 | A1H3R1R2 | 0.95229 |
5M7M 04 | 4 | A1H1H2H3 | 0.47716 |
5MHP 01 | 6 | A1H1H2H3H4H5 | 3.6354 |
5MHP 02 | 6 | A1H1H2H3H4H6 | 3.6354 |
5MHP 03 | 6 | A1H1H2H4H6R2 | 2.8903 |
5MHP 04 | 6 | A1H1H3H4H6R2 | 2.8903 |
5MHP 05 | 5 | A1H1H3H4H5 | 2.4170 |
5MHP 06 | 5 | A1H1H2H3H4 | 2.4170 |
5MHP 07 | 5 | A1H1H2H4H5 | 2.4170 |
5MHP 08 | 5 | A1H1H3H4H6 | 2.4170 |
5MHP 09 | 5 | A1H1H2H4H6 | 2.4170 |
5MHP 10 | 5 | A1H1H4H6R2 | 2.3270 |
Verification with Known Inactives/actives | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|
Pharmacophore | TAa | TIb | TPc | TNd | FPe | FNf | SEg | SPh | Qi | ROC |
5M7M 01 | 34 | 6396 | 34 | 4737 | 1659 | 0 | 1 | 0.741 | 0.742 | 0.845 |
5M7M 02 | 34 | 6396 | 34 | 4108 | 2288 | 0 | 1 | 0.642 | 0.6442 | 0.770 |
5M7M 03 | 34 | 6396 | 34 | 4002 | 2394 | 0 | 1 | 0.626 | 0.628 | 0.793 |
5M7M 04 | 34 | 6396 | 34 | 3991 | 2405 | 0 | 1 | 0.624 | 0.626 | 0.773 |
5MHP 01 | 34 | 6396 | 19 | 6172 | 224 | 15 | 0.559 | 0.965 | 0.963 | 0.766 |
5MHP 02 | 34 | 6396 | 26 | 6219 | 177 | 8 | 0.765 | 0.972 | 0.971 | 0.866 |
5MHP 03 | 34 | 6396 | 33 | 6093 | 303 | 1 | 0.971 | 0.953 | 0.953 | 0.967 |
5MHP 04 | 34 | 6396 | 28 | 6155 | 241 | 6 | 0.824 | 0.962 | 0.962 | 0.894 |
5MHP 05 | 34 | 6396 | 25 | 5773 | 623 | 9 | 0.735 | 0.903 | 0.902 | 0.829 |
5MHP 06 | 34 | 6396 | 34 | 5634 | 762 | 0 | 1 | 0.881 | 0.881 | 0.969 |
5MHP 07 | 34 | 6396 | 34 | 5590 | 806 | 0 | 1 | 0.874 | 0.875 | 0.943 |
5MHP 08 | 34 | 6396 | 32 | 5845 | 551 | 2 | 0.941 | 0.914 | 0.914 | 0.927 |
5MHP 09 | 34 | 6396 | 34 | 5788 | 608 | 0 | 1 | 0.905 | 0.905 | 0.959 |
5MHP 10 | 34 | 6396 | 34 | 5650 | 746 | 0 | 1 | 0.883 | 0.884 | 0.951 |
Ligand IDa | PDB Entry | RMSD (Å) |
---|---|---|
7HR | 5M7M | 1.8001 |
7NB | 5MHP | 0.6007 |
Compound | Fit Value | Docking Score | Predicted Activity (pIC50) |
---|---|---|---|
cpd1 | 2.95497 | 37.0191 | 5.6312 |
cpd2 | 2.33815 | 43.5524 | 5.63735 |
cpd3 | 2.08654 | 34.011 | 5.687 |
cpd4 | 2.00695 | 48.8647 | 5.62577 |
cpd5 | 3.63318 | 42.5693 | 5.71689 |
cpd6 | 3.55526 | 34.2583 | 5.75721 |
cpd7 | 3.14614 | 33.264 | 5.74321 |
cpd8 | 3.12769 | 40.4997 | 5.68862 |
cpd9 | 2.53449 | 35.5562 | 5.76814 |
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Ren, J.-X.; Zhang, R.-T.; Zhang, H. Identifying Novel ATX Inhibitors via Combinatory Virtual Screening Using Crystallography-Derived Pharmacophore Modelling, Docking Study, and QSAR Analysis. Molecules 2020, 25, 1107. https://doi.org/10.3390/molecules25051107
Ren J-X, Zhang R-T, Zhang H. Identifying Novel ATX Inhibitors via Combinatory Virtual Screening Using Crystallography-Derived Pharmacophore Modelling, Docking Study, and QSAR Analysis. Molecules. 2020; 25(5):1107. https://doi.org/10.3390/molecules25051107
Chicago/Turabian StyleRen, Ji-Xia, Rui-Tao Zhang, and Hui Zhang. 2020. "Identifying Novel ATX Inhibitors via Combinatory Virtual Screening Using Crystallography-Derived Pharmacophore Modelling, Docking Study, and QSAR Analysis" Molecules 25, no. 5: 1107. https://doi.org/10.3390/molecules25051107
APA StyleRen, J. -X., Zhang, R. -T., & Zhang, H. (2020). Identifying Novel ATX Inhibitors via Combinatory Virtual Screening Using Crystallography-Derived Pharmacophore Modelling, Docking Study, and QSAR Analysis. Molecules, 25(5), 1107. https://doi.org/10.3390/molecules25051107