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
pagine (da-a)-
Numero di pagine6
RivistaACS Medicinal Chemistry Letters
Stato di pubblicazionePublished - 2019

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Organic Chemistry
  • Drug Discovery

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 = "computational mutagenesis; Induced fit docking; MM-GBSA; oxadiazoles; premature termination codons; QPLD; Biochemistry; Drug Discovery3003 Pharmaceutical Science; Organic Chemistry",
author = "Almerico, {Anna Maria} and Andrea Pace and Ivana Pibiri and Laura Lentini and Marco Tutone",
year = "2019",
language = "English",
pages = "--",
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 - Almerico, Anna Maria

AU - Pace, Andrea

AU - Pibiri, Ivana

AU - Lentini, Laura

AU - Tutone, Marco

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 - computational mutagenesis; Induced fit docking; MM-GBSA; oxadiazoles; premature termination codons; QPLD; Biochemistry; Drug Discovery3003 Pharmaceutical Science; Organic Chemistry

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

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

M3 - Article

SP - -

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

SN - 1948-5875

ER -