Homology Model and Docking-Based Virtual Screening for Ligands of Human Dyskerin as New Inhibitors of Telomerase for Cancer Treatment
Abstract
:1. Introduction
2. Results
2.1. Physicochemical Properties and the Abundance of aa in hDKC1 Protein
2.2. Prediction of the Two-Dimensional Structure of hDKC1
2.3. Sequence and Secondary Structure Analysis between hDKC1 and Saccharomyces Cerevisiae Dyskerin
2.4. Predicted 3D Homology Model of hDKC1 by I-TASSER
2.5. 3D Structure Validation
2.6. Study of Mutation Stability
2.7. Evaluation and Recognition of Hydrophobic Pockets on hDKC1 Model
2.8. Study and Determination of the Hydrophobic Pocket Containing the Mutation K314
2.9. Docking Based Virtual Screening on the hDKC1 Model by AutoDock Vina
2.10. In Vitro Screening of the Candidate Compounds by Telomerase Activity Assay
3. Discussion
4. Materials and Methods
4.1. Sequence Obtaining and Physicochemical Parameters Analysis of hDKC1
4.2. Secondary Structure Prediction
4.3. Modelling of 3D Structure of hDKC1
4.4. Validation of the Generated Model
4.5. Mutation Stability Analysis
4.6. Hydrophobic Pockets Identification
4.7. Docking Based Virtual Screening
4.8. Cell Line and Culture Conditions
4.9. Determination of Telomerase Activity
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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hDKC1 Model | C-Score | TM Score | RMSD (Å) |
---|---|---|---|
Homology Model | −0.09 | 0.70 ± 0.12 | 7.1 ± 4.2 |
Ab initio model | −2.32 | 0.44 ± 0.14 | 13.0 ± 4.2 |
Relevance (%) | Volume (Å3) | Residue Number | |
---|---|---|---|
1 | 100 | 615 | 96, 101, 102, 103, 122, 123, 124, 125, 126, 128, 129, 130, 131, 132, 153, 187, 188, 246, 248 |
2 | 94 | 203 | 299, 300, 301, 314, 315, 317, 320, 322, 323, 350, 354, 355, 358, 360, 361, 362, 363 |
3 | 79 | 284 | 81, 85, 88, 89, 138, 289, 290, 341, 342, 370, 371, 372, 375 |
4 | 69 | 926 | 259, 260, 261, 265, 272, 280, 281, 284, 285, 287 |
5 | 69 | 289 | 141, 142, 144, 145, 293, 296, 332, 333, 334, 344, 345, 346, 367, 368, 370 |
6 | 64 | 810 | 74, 75, 76, 80, 81, 82, 85, 88, 341, 372, 375 |
7 | 60 | 208 | 54, 91, 93, 254, 258, 259, 261, 284, 285, 287, 288, 289, 291, 292, |
8 | 60 | 444 | 70, 71, 72, 303, 304, 307, 376, 377, 378, 379, 380, |
9 | 58 | 100 | 157, 169, 170, 173, 204, 206, 207, 214, 215, 216, 233 |
10 | 57 | 367 | 98, 127, 129, 154, 155, 156, 215, 245, 246, 247, 249, 256 |
11 | 57 | 994 | 183, 184, 185, 186, 192, 227, 228, 231, 241, 242, 243 |
12 | 54 | 525 | 54, 55, 57, 58, 294, 295, 296, 297, 298, 324 |
13 | 47 | 580 | 301, 302, 304, 305, 308, 309, 313, 314, 315, 316, 318, 319, 378 |
14 | 47 | 158 | 53, 54, 55, 56, 77, 78, 79, 80, 290, 339, 340 |
15 | 44 | 92 | 83, 86, 87, 273, 278, 279, 282, 283 |
16 | 42 | 146 | 176, 180, 181, 182, 197, 199, 218, 220, 224, 225, 226, 228, 229, 232 |
17 | 40 | 295 | 103, 119, 120, 121, 122, 123, 124, 143, 147, 151, 222, 223 |
18 | 37 | 268 | 98, 125, 126, 127, 128, 187, 227, 243, 244, 245, 246 |
19 | 33 | 274 | 156, 206, 207, 208, 211, 213, 214, 215 |
20 | 32 | 425 | 83, 84, 87, 113, 114, 115, 137, 270, 273, 274, 282 |
21 | 28 | 374 | 138, 141, 310, 311, 369, 371, 372, 373, 374 |
Name | Compound | Docking Energy (kcal/mol) | SD | Name | Compound | Docking Energy (kcal/mol) | SD |
---|---|---|---|---|---|---|---|
E1 | −7.20 | 0.21 | E6 | −6.73 | 0.21 | ||
E2 | −7.11 | 0.08 | E7 | −6.69 | 0.11 | ||
E3 | 7.04 | 0.06 | E8 | −6.59 | 0.25 | ||
E4 | −6.93 | 0.13 | E9 | −6.54 | 0.09 | ||
E5 | −6.81 | 0.17 | E10 | −6.52 | 0.45 |
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Armando, R.G.; Mengual Gómez, D.L.; Juritz, E.I.; Lorenzano Menna, P.; Gomez, D.E. Homology Model and Docking-Based Virtual Screening for Ligands of Human Dyskerin as New Inhibitors of Telomerase for Cancer Treatment. Int. J. Mol. Sci. 2018, 19, 3216. https://doi.org/10.3390/ijms19103216
Armando RG, Mengual Gómez DL, Juritz EI, Lorenzano Menna P, Gomez DE. Homology Model and Docking-Based Virtual Screening for Ligands of Human Dyskerin as New Inhibitors of Telomerase for Cancer Treatment. International Journal of Molecular Sciences. 2018; 19(10):3216. https://doi.org/10.3390/ijms19103216
Chicago/Turabian StyleArmando, Romina Gabriela, Diego Luis Mengual Gómez, Ezequiel Ivan Juritz, Pablo Lorenzano Menna, and Daniel Eduardo Gomez. 2018. "Homology Model and Docking-Based Virtual Screening for Ligands of Human Dyskerin as New Inhibitors of Telomerase for Cancer Treatment" International Journal of Molecular Sciences 19, no. 10: 3216. https://doi.org/10.3390/ijms19103216