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dc.contributor.author
Maggio, Julián Francisco
dc.contributor.author
Cabrera, Maia Diana Eliana
dc.contributor.author
Armando, Romina Gabriela
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Chinestrad, Patricio Manuel
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Pifano, Marina
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Lorenzano Menna, Pablo
dc.contributor.author
Gomez, Daniel Eduardo
dc.contributor.author
Mengual Gómez, Diego Luis
dc.date.available
2022-08-03T12:33:25Z
dc.date.issued
2021-01
dc.identifier.citation
Maggio, Julián Francisco; Cabrera, Maia Diana Eliana; Armando, Romina Gabriela; Chinestrad, Patricio Manuel; Pifano, Marina; et al.; Rational design of PIN1 inhibitors for cancer treatment based on conformational diversity analysis and docking based virtual screening; Adenine Press; Journal Of Biomolecular Structure & Dynamics; 40; 13; 1-2021; 5858-5867
dc.identifier.issn
0739-1102
dc.identifier.uri
http://hdl.handle.net/11336/163992
dc.description.abstract
The parvulin PIN1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1), is the only enzyme capable of isomerizing prolines of phospho-Serine/Threonine-Proline motifs. PIN1 binds to a subset of proteins and plays an essential role in regulating protein function post-phosphorylation control. Furthermore, the activity of PIN1 regulates the outcome of the signalling of proline-directed kinases (e.g. MAPK, CDK, or GSK3) and thus regulates cell proliferation and cell survival. For these reasons, PIN1 inhibitors are interesting since they may have therapeutic implications for cancer. Several authors have already reported that the non-structural point mutation Trp34Ala prevents PIN1 from interacting with its downstream effector proteins. In this work, we characterized PIN1 structurally, intending to explore new inhibition targets for the rational design of pharmacological activity compounds. Through a conformational diversity analysis of PIN1, we identified and characterized a highly specific druggable pocket around the residue Trp34. This pocket was used in a high-throughput docking screening of 450,000 drug-like compounds, and the top 10 were selected for re-docking studies on the previously used conformers. Finally, we evaluated the binding of each compound by thermal shift assay and found four molecules with a high affinity for PIN1 and potential inhibitory activity. Through this strategy, we achieved novel drug candidates with the ability to interfere with the phosphorylation-dependent actions of PIN1 and with potential applications in the treatment of cancer.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Adenine Press
dc.rights
info:eu-repo/semantics/restrictedAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
CANCER
dc.subject
CONFORMATIONAL DIVERSITY
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DRUG DESIGN
dc.subject
PIN1 INHIBITORS
dc.subject.classification
Bioquímica y Biología Molecular
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Ciencias Biológicas
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CIENCIAS NATURALES Y EXACTAS
dc.title
Rational design of PIN1 inhibitors for cancer treatment based on conformational diversity analysis and docking based virtual screening
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2022-08-01T13:36:12Z
dc.identifier.eissn
1538-0254
dc.journal.volume
40
dc.journal.number
13
dc.journal.pagination
5858-5867
dc.journal.pais
Estados Unidos
dc.description.fil
Fil: Maggio, Julián Francisco. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
dc.description.fil
Fil: Cabrera, Maia Diana Eliana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Farmacología Molecular; Argentina
dc.description.fil
Fil: Armando, Romina Gabriela. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil
Fil: Chinestrad, Patricio Manuel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Farmacología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil
Fil: Pifano, Marina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil
Fil: Lorenzano Menna, Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Farmacología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil
Fil: Gomez, Daniel Eduardo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil
Fil: Mengual Gómez, Diego Luis. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.journal.title
Journal Of Biomolecular Structure & Dynamics
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.tandfonline.com/doi/full/10.1080/07391102.2021.1874531
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/https://doi.org/10.1080/07391102.2021.1874531
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