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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 evolutionary l...

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Autores principales: Vlachakis, Dimitrios, Pavlopoulou, Athanasia, Tsiliki, Georgia, Komiotis, Dimitri, Stathopoulos, Constantinos, Balatsos, Nikolaos A. A., Kossida, Sophia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516499/
https://www.ncbi.nlm.nih.gov/pubmed/23236441
http://dx.doi.org/10.1371/journal.pone.0051113
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author Vlachakis, Dimitrios
Pavlopoulou, Athanasia
Tsiliki, Georgia
Komiotis, Dimitri
Stathopoulos, Constantinos
Balatsos, Nikolaos A. A.
Kossida, Sophia
author_facet Vlachakis, Dimitrios
Pavlopoulou, Athanasia
Tsiliki, Georgia
Komiotis, Dimitri
Stathopoulos, Constantinos
Balatsos, Nikolaos A. A.
Kossida, Sophia
author_sort Vlachakis, Dimitrios
collection PubMed
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.
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spelling pubmed-35164992012-12-12 An Integrated In Silico Approach to Design Specific Inhibitors Targeting Human Poly(A)-Specific Ribonuclease Vlachakis, Dimitrios Pavlopoulou, Athanasia Tsiliki, Georgia Komiotis, Dimitri Stathopoulos, Constantinos Balatsos, Nikolaos A. A. Kossida, Sophia PLoS One Research Article 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. Public Library of Science 2012-12-06 /pmc/articles/PMC3516499/ /pubmed/23236441 http://dx.doi.org/10.1371/journal.pone.0051113 Text en © 2012 Vlachakis et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Vlachakis, Dimitrios
Pavlopoulou, Athanasia
Tsiliki, Georgia
Komiotis, Dimitri
Stathopoulos, Constantinos
Balatsos, Nikolaos A. A.
Kossida, Sophia
An Integrated In Silico Approach to Design Specific Inhibitors Targeting Human Poly(A)-Specific Ribonuclease
title 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_short 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
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516499/
https://www.ncbi.nlm.nih.gov/pubmed/23236441
http://dx.doi.org/10.1371/journal.pone.0051113
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