An integrated in silico approach to design specific inhibitors targeting human poly(a)-specific ribonuclease.

Poly(A)-specific ribonuclease (PARN) is an exoribonuclease/deadenylase that degrades 3'-end poly(A) tails in almost all eukaryotic organisms. Much of the biochemical and structural information on PARN comes from the human enzyme. However, the existence of PARN all along the eukaryotic evolution...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Dimitrios Vlachakis, Athanasia Pavlopoulou, Georgia Tsiliki, Dimitri Komiotis, Constantinos Stathopoulos, Nikolaos A A Balatsos, Sophia Kossida
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6ff85b5750a040839623b0614edc0503
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:6ff85b5750a040839623b0614edc0503
record_format	dspace
spelling	oai:doaj.org-article:6ff85b5750a040839623b0614edc05032021-11-18T08:06:08ZAn integrated in silico approach to design specific inhibitors targeting human poly(a)-specific ribonuclease.1932-620310.1371/journal.pone.0051113https://doaj.org/article/6ff85b5750a040839623b0614edc05032012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23236441/?tool=EBIhttps://doaj.org/toc/1932-6203Poly(A)-specific ribonuclease (PARN) is an exoribonuclease/deadenylase that degrades 3'-end poly(A) tails in almost all eukaryotic organisms. Much of the biochemical and structural information on PARN comes from the human enzyme. However, the existence of PARN all along the eukaryotic evolutionary ladder requires further and thorough investigation. Although the complete structure of the full-length human PARN, as well as several aspects of the catalytic mechanism still remain elusive, many previous studies indicate that PARN can be used as potent and promising anti-cancer target. In the present study, we attempt to complement the existing structural information on PARN with in-depth bioinformatics analyses, in order to get a hologram of the molecular evolution of PARNs active site. In an effort to draw an outline, which allows specific drug design targeting PARN, an unequivocally specific platform was designed for the development of selective modulators focusing on the unique structural and catalytic features of the enzyme. Extensive phylogenetic analysis based on all the publicly available genomes indicated a broad distribution for PARN across eukaryotic species and revealed structurally important amino acids which could be assigned as potentially strong contributors to the regulation of the catalytic mechanism of PARN. Based on the above, we propose a comprehensive in silico model for the PARN's catalytic mechanism and moreover, we developed a 3D pharmacophore model, which was subsequently used for the introduction of DNP-poly(A) amphipathic substrate analog as a potential inhibitor of PARN. Indeed, biochemical analysis revealed that DNP-poly(A) inhibits PARN competitively. Our approach provides an efficient integrated platform for the rational design of pharmacophore models as well as novel modulators of PARN with therapeutic potential.Dimitrios VlachakisAthanasia PavlopoulouGeorgia TsilikiDimitri KomiotisConstantinos StathopoulosNikolaos A A BalatsosSophia KossidaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 12, p e51113 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Dimitrios Vlachakis Athanasia Pavlopoulou Georgia Tsiliki Dimitri Komiotis Constantinos Stathopoulos Nikolaos A A Balatsos Sophia Kossida An integrated in silico approach to design specific inhibitors targeting human poly(a)-specific ribonuclease.
description	Poly(A)-specific ribonuclease (PARN) is an exoribonuclease/deadenylase that degrades 3'-end poly(A) tails in almost all eukaryotic organisms. Much of the biochemical and structural information on PARN comes from the human enzyme. However, the existence of PARN all along the eukaryotic evolutionary ladder requires further and thorough investigation. Although the complete structure of the full-length human PARN, as well as several aspects of the catalytic mechanism still remain elusive, many previous studies indicate that PARN can be used as potent and promising anti-cancer target. In the present study, we attempt to complement the existing structural information on PARN with in-depth bioinformatics analyses, in order to get a hologram of the molecular evolution of PARNs active site. In an effort to draw an outline, which allows specific drug design targeting PARN, an unequivocally specific platform was designed for the development of selective modulators focusing on the unique structural and catalytic features of the enzyme. Extensive phylogenetic analysis based on all the publicly available genomes indicated a broad distribution for PARN across eukaryotic species and revealed structurally important amino acids which could be assigned as potentially strong contributors to the regulation of the catalytic mechanism of PARN. Based on the above, we propose a comprehensive in silico model for the PARN's catalytic mechanism and moreover, we developed a 3D pharmacophore model, which was subsequently used for the introduction of DNP-poly(A) amphipathic substrate analog as a potential inhibitor of PARN. Indeed, biochemical analysis revealed that DNP-poly(A) inhibits PARN competitively. Our approach provides an efficient integrated platform for the rational design of pharmacophore models as well as novel modulators of PARN with therapeutic potential.
format	article
author	Dimitrios Vlachakis Athanasia Pavlopoulou Georgia Tsiliki Dimitri Komiotis Constantinos Stathopoulos Nikolaos A A Balatsos Sophia Kossida
author_facet	Dimitrios Vlachakis Athanasia Pavlopoulou Georgia Tsiliki Dimitri Komiotis Constantinos Stathopoulos Nikolaos A A Balatsos Sophia Kossida
author_sort	Dimitrios Vlachakis
title	An integrated in silico approach to design specific inhibitors targeting human poly(a)-specific ribonuclease.
title_short	An integrated in silico approach to design specific inhibitors targeting human poly(a)-specific ribonuclease.
title_full	An integrated in silico approach to design specific inhibitors targeting human poly(a)-specific ribonuclease.
title_fullStr	An integrated in silico approach to design specific inhibitors targeting human poly(a)-specific ribonuclease.
title_full_unstemmed	An integrated in silico approach to design specific inhibitors targeting human poly(a)-specific ribonuclease.
title_sort	integrated in silico approach to design specific inhibitors targeting human poly(a)-specific ribonuclease.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/6ff85b5750a040839623b0614edc0503
work_keys_str_mv	AT dimitriosvlachakis anintegratedinsilicoapproachtodesignspecificinhibitorstargetinghumanpolyaspecificribonuclease AT athanasiapavlopoulou anintegratedinsilicoapproachtodesignspecificinhibitorstargetinghumanpolyaspecificribonuclease AT georgiatsiliki anintegratedinsilicoapproachtodesignspecificinhibitorstargetinghumanpolyaspecificribonuclease AT dimitrikomiotis anintegratedinsilicoapproachtodesignspecificinhibitorstargetinghumanpolyaspecificribonuclease AT constantinosstathopoulos anintegratedinsilicoapproachtodesignspecificinhibitorstargetinghumanpolyaspecificribonuclease AT nikolaosaabalatsos anintegratedinsilicoapproachtodesignspecificinhibitorstargetinghumanpolyaspecificribonuclease AT sophiakossida anintegratedinsilicoapproachtodesignspecificinhibitorstargetinghumanpolyaspecificribonuclease AT dimitriosvlachakis integratedinsilicoapproachtodesignspecificinhibitorstargetinghumanpolyaspecificribonuclease AT athanasiapavlopoulou integratedinsilicoapproachtodesignspecificinhibitorstargetinghumanpolyaspecificribonuclease AT georgiatsiliki integratedinsilicoapproachtodesignspecificinhibitorstargetinghumanpolyaspecificribonuclease AT dimitrikomiotis integratedinsilicoapproachtodesignspecificinhibitorstargetinghumanpolyaspecificribonuclease AT constantinosstathopoulos integratedinsilicoapproachtodesignspecificinhibitorstargetinghumanpolyaspecificribonuclease AT nikolaosaabalatsos integratedinsilicoapproachtodesignspecificinhibitorstargetinghumanpolyaspecificribonuclease AT sophiakossida integratedinsilicoapproachtodesignspecificinhibitorstargetinghumanpolyaspecificribonuclease
_version_	1718422234202112000

An integrated in silico approach to design specific inhibitors targeting human poly(a)-specific ribonuclease.

Ejemplares similares