Deciphering the Nonsense Readthrough Mechanism of Action of Ataluren: An in Silico Compared Study

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2 Citazioni (Scopus)

Abstract

Ataluren was reported to suppress nonsense mutations by promoting the readthrough of premature stop codons, although its mechanism of action (MOA) is still debated. The likely interaction of Ataluren with CFTR-mRNA has been previously studied by molecular dynamics. In this work we extended the modeling of Ataluren's MOA by complementary computational approaches such as induced fit docking (IFD), quantum polarized ligand docking (QPLD), MM-GBSA free-energy calculations, and computational mutagenesis. In addition to CFTR-mRNA, this study considered other model targets implicated in the translation process, such as eukaryotic rRNA 18S, prokaryotic rRNA 16S, and eukaryotic Release Factor 1 (eRF1), and we performed a comparison with a new promising Ataluren analogue (NV2445) and with a series of aminoglycosides, known to suppress the normal proofreading function of the ribosome. Results confirmed mRNA as the most likely candidate target for Ataluren and its analogue, and binding energies calculated after computational mutagenesis highlighted how Ataluren's interaction with the premature stop codon could be affected by ancillary nucleotides in the genetic context.
Lingua originaleEnglish
Numero di pagine6
RivistaACS Medicinal Chemistry Letters
Stato di pubblicazionePublished - 2019

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Computer Simulation
Nonsense Codon
Mutagenesis
Messenger RNA
Aminoglycosides
Molecular Dynamics Simulation
Binding energy
Ribosomes
Free energy
Molecular dynamics
ataluren
Nucleotides
Ligands

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Cita questo

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title = "Deciphering the Nonsense Readthrough Mechanism of Action of Ataluren: An in Silico Compared Study",
abstract = "Ataluren was reported to suppress nonsense mutations by promoting the readthrough of premature stop codons, although its mechanism of action (MOA) is still debated. The likely interaction of Ataluren with CFTR-mRNA has been previously studied by molecular dynamics. In this work we extended the modeling of Ataluren's MOA by complementary computational approaches such as induced fit docking (IFD), quantum polarized ligand docking (QPLD), MM-GBSA free-energy calculations, and computational mutagenesis. In addition to CFTR-mRNA, this study considered other model targets implicated in the translation process, such as eukaryotic rRNA 18S, prokaryotic rRNA 16S, and eukaryotic Release Factor 1 (eRF1), and we performed a comparison with a new promising Ataluren analogue (NV2445) and with a series of aminoglycosides, known to suppress the normal proofreading function of the ribosome. Results confirmed mRNA as the most likely candidate target for Ataluren and its analogue, and binding energies calculated after computational mutagenesis highlighted how Ataluren's interaction with the premature stop codon could be affected by ancillary nucleotides in the genetic context.",
keywords = "Biochemistry, Drug Discovery3003 Pharmaceutical Science, Induced fit docking, MM-GBSA, Organic Chemistry, QPLD, computational mutagenesis, oxadiazoles, premature termination codons",
author = "Marco Tutone and Andrea Pace and Ivana Pibiri and Laura Lentini and Almerico, {Anna Maria}",
year = "2019",
language = "English",
journal = "ACS Medicinal Chemistry Letters",
issn = "1948-5875",
publisher = "American Chemical Society",

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TY - JOUR

T1 - Deciphering the Nonsense Readthrough Mechanism of Action of Ataluren: An in Silico Compared Study

AU - Tutone, Marco

AU - Pace, Andrea

AU - Pibiri, Ivana

AU - Lentini, Laura

AU - Almerico, Anna Maria

PY - 2019

Y1 - 2019

N2 - Ataluren was reported to suppress nonsense mutations by promoting the readthrough of premature stop codons, although its mechanism of action (MOA) is still debated. The likely interaction of Ataluren with CFTR-mRNA has been previously studied by molecular dynamics. In this work we extended the modeling of Ataluren's MOA by complementary computational approaches such as induced fit docking (IFD), quantum polarized ligand docking (QPLD), MM-GBSA free-energy calculations, and computational mutagenesis. In addition to CFTR-mRNA, this study considered other model targets implicated in the translation process, such as eukaryotic rRNA 18S, prokaryotic rRNA 16S, and eukaryotic Release Factor 1 (eRF1), and we performed a comparison with a new promising Ataluren analogue (NV2445) and with a series of aminoglycosides, known to suppress the normal proofreading function of the ribosome. Results confirmed mRNA as the most likely candidate target for Ataluren and its analogue, and binding energies calculated after computational mutagenesis highlighted how Ataluren's interaction with the premature stop codon could be affected by ancillary nucleotides in the genetic context.

AB - Ataluren was reported to suppress nonsense mutations by promoting the readthrough of premature stop codons, although its mechanism of action (MOA) is still debated. The likely interaction of Ataluren with CFTR-mRNA has been previously studied by molecular dynamics. In this work we extended the modeling of Ataluren's MOA by complementary computational approaches such as induced fit docking (IFD), quantum polarized ligand docking (QPLD), MM-GBSA free-energy calculations, and computational mutagenesis. In addition to CFTR-mRNA, this study considered other model targets implicated in the translation process, such as eukaryotic rRNA 18S, prokaryotic rRNA 16S, and eukaryotic Release Factor 1 (eRF1), and we performed a comparison with a new promising Ataluren analogue (NV2445) and with a series of aminoglycosides, known to suppress the normal proofreading function of the ribosome. Results confirmed mRNA as the most likely candidate target for Ataluren and its analogue, and binding energies calculated after computational mutagenesis highlighted how Ataluren's interaction with the premature stop codon could be affected by ancillary nucleotides in the genetic context.

KW - Biochemistry

KW - Drug Discovery3003 Pharmaceutical Science

KW - Induced fit docking

KW - MM-GBSA

KW - Organic Chemistry

KW - QPLD

KW - computational mutagenesis

KW - oxadiazoles

KW - premature termination codons

UR - http://hdl.handle.net/10447/348103

UR - http://pubs.acs.org/journal/amclct

M3 - Article

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

SN - 1948-5875

ER -