Dynamic Structure-Based Pharmacophore Model Development: A New and Effective Addition in the Histone Deacetylase 8 (HDAC8) Inhibitor Discovery
Abstract
:1. Introduction
2. Results and Discussion
2.1. Molecular Dynamic Simulation Studies
2.2. Structure-Based Pharmacophore Models
2.3. Validation of Generated Pharmacophore Models
2.4. Database Screening
2.5. Molecular Docking
3. Experimental Section
3.1. Selection of Protein and Inhibitor Structures
3.2. Molecular Docking and Dynamic Simulations
3.3. Clustering of Snapshots
3.4. Structure-Based Pharmacophore Generation and Validation
3.5. Database Screening
3.6. Molecular Docking and Lead Identification
4. Conclusions
Supplementary Material
ijms-12-09440-s001.pdfAcknowledgements
References
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HDAC8 Dataset | Total | Pharm-A | Pharm-B | Pharm-X | |||
---|---|---|---|---|---|---|---|
Screened | Percentage (%) | Screened | Percentage (%) | Screened | Percentage (%) | ||
Total | 100 | 52 | 52 | 57 | 57 | 18 | 18 |
Active <0.1 μM | 17 | 15 | 88.24 | 13 | 76.47 | 9 | 52.94 |
Moderately active ≥0.1 <1 μM | 68 | 35 | 51.47 | 40 | 58.82 | 8 | 11.76 |
Inactive >1 μM | 15 | 2 | 13.33 | 4 | 26.66 | 1 | 6.66 |
PDB ID | Resolution (Å) | Bound Ligand | Mutation | Metal Ion |
---|---|---|---|---|
1T64 | 1.90 | Trichostatin A | - | Zn2+ |
1T67 | 2.31 | M344 | - | Zn2+ |
1T69 | 2.91 | SAHA | - | Zn2+ |
1VKG | 2.20 | CRA-19156 | - | Zn2+ |
1W22 | 2.50 | NHB | - | Zn2+ |
2V5W | 2.00 | Substrate | - | Zn2+ |
2V5X | 2.25 | V5X | - | Zn2+ |
3EW8 | 1.80 | M344 | D101L | Zn2+ |
3EWF | 2.50 | Substrate | H143A | Zn2+ |
3EZP | 2.65 | M344 | D101N | Zn2+ |
3EZT | 2.85 | M344 | D101E | Zn2+ |
3F06 | 2.55 | M344 | D101A | Zn2+ |
3F07 | 3.30 | APHA | - | Zn2+ |
3F0R | 2.54 | Trichostatin A | - | Zn2+ |
3MZ3 | 3.20 | M344 | - | Co2+ |
3MZ4 | 1.85 | M344 | D101L | Mn2+ |
3MZ6 | 2.00 | M344 | D101L | Fe2+ |
3MZ7 | 1.90 | M344 | D101L | Co2+ |
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Thangapandian, S.; John, S.; Lee, Y.; Kim, S.; Lee, K.W. Dynamic Structure-Based Pharmacophore Model Development: A New and Effective Addition in the Histone Deacetylase 8 (HDAC8) Inhibitor Discovery. Int. J. Mol. Sci. 2011, 12, 9440-9462. https://doi.org/10.3390/ijms12129440
Thangapandian S, John S, Lee Y, Kim S, Lee KW. Dynamic Structure-Based Pharmacophore Model Development: A New and Effective Addition in the Histone Deacetylase 8 (HDAC8) Inhibitor Discovery. International Journal of Molecular Sciences. 2011; 12(12):9440-9462. https://doi.org/10.3390/ijms12129440
Chicago/Turabian StyleThangapandian, Sundarapandian, Shalini John, Yuno Lee, Songmi Kim, and Keun Woo Lee. 2011. "Dynamic Structure-Based Pharmacophore Model Development: A New and Effective Addition in the Histone Deacetylase 8 (HDAC8) Inhibitor Discovery" International Journal of Molecular Sciences 12, no. 12: 9440-9462. https://doi.org/10.3390/ijms12129440