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Open AccessArticle

Homology Model and Docking-Based Virtual Screening for Ligands of Human Dyskerin as New Inhibitors of Telomerase for Cancer Treatment

1
Laboratory of Molecular Oncology, Department of Science and Technology, Quilmes National University, Buenos Aires B1876BXD, Argentina
2
Center for Bioinformatics and Integrative Biology, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago 8370146, Chile
3
Laboratory of Molecular Pharmacology, Department of Science and Technology, Quilmes National University, Buenos Aires B1876BXD, Argentina
*
Author to whom correspondence should be addressed.
The authors have contributed equally to the work.
Int. J. Mol. Sci. 2018, 19(10), 3216; https://doi.org/10.3390/ijms19103216
Received: 11 September 2018 / Revised: 6 October 2018 / Accepted: 8 October 2018 / Published: 18 October 2018
(This article belongs to the Section Molecular Biophysics)
Immortality is one of the main features of cancer cells. Tumor cells have an unlimited replicative potential, principally due to the holoenzyme telomerase. Telomerase is composed mainly by dyskerin (DKC1), a catalytic retrotranscriptase (hTERT) and an RNA template (hTR). The aim of this work is to develop new inhibitors of telomerase, selecting the interaction between hTR–DKC1 as a target. We designed two models of the human protein DKC1: homology and ab initio. These models were evaluated by different procedures, revealing that the homology model parameters were the most accurate. We selected two hydrophobic pockets contained in the PUA (pseudouridine synthase and archaeosine transglycosylase) domain, using structural and stability analysis. We carried out a docking-based virtual screen on these pockets, using the reported mutation K314 as the center of the docking. The hDKC1 model was tested against a library of 450,000 drug-like molecules. We selected the first 10 molecules that showed the highest affinity values to test their inhibitory activity on the cell line MDA MB 231 (Monroe Dunaway Anderson Metastasis Breast cancer 231), obtaining three compounds that showed inhibitory effect. These results allowed us to validate our design and set the basis to continue with the study of telomerase inhibitors for cancer treatment. View Full-Text
Keywords: telomerase; DKC1; hTR; inhibitors; cancer telomerase; DKC1; hTR; inhibitors; cancer
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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.

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