Homology model and docking-based virtual screening for ligands of human dyskerin as new inhibitors of telomerase for cancer treatment

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dc.contributor.authorArmando, R.G.
dc.contributor.authorGómez, D.L.M.
dc.contributor.authorJuritz, E.I.
dc.contributor.authorMenna, P.L.
dc.contributor.authorGomez, D.E.
dc.date.accessioned2019-12-11T15:36:52Z
dc.date.available2019-12-11T15:36:52Z
dc.date.issued2018-10
dc.descriptionIndexación: Scopus.es
dc.descriptionFunding: This research was funded by Quilmes National University, grant number PUNQ 1398/15 and by Cancer National Institute (Argentina), grant number EXPTE 756/16.
dc.descriptionAcknowledgments: The present study was supported by grants from Quilmes National University, National Research Council (CONICET), the National Agency for the Promotion of Science and Technology (ANPCyT) and Cancer National Institute (Argentina). Daniel Eduardo Gomez, Diego Mengual Gómez, Pablo Lorenzano Menna and Ezequiel Juritz are members of CONICET. Romina Armando is a postdoctoral fellow from CONICET. The authors wish to express their gratitude to Tadeo Saldaño for critical reading of the manuscript and to Andrii Buvailo from Enamine for his continuous support.
dc.description.abstractImmortality 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. © 2018 by the authors. Licensee MDPI, Basel, Switzerland.es
dc.description.urihttps://www.mdpi.com/1422-0067/19/10/3216
dc.identifier.citationInternational Journal of Molecular Sciences, 19(10), art. no. 3216.es
dc.identifier.issn1661-6596
dc.identifier.otherDOI: 10.3390/ijms19103216
dc.identifier.urihttp://repositorio.unab.cl/xmlui/handle/ria/11376
dc.language.isoenes
dc.publisherMDPI AGes
dc.subjectCanceres
dc.subjectDKC1es
dc.subjecthTRes
dc.subjectInhibitorses
dc.subjectTelomerasees
dc.titleHomology model and docking-based virtual screening for ligands of human dyskerin as new inhibitors of telomerase for cancer treatmentes
dc.typeArtículoes
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