期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 10, 期 4, 页码 522-527出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.8b00558
关键词
Induced fit docking; QPLD; MM-GBSA; computational mutagenesis; oxadiazoles; premature termination codons
资金
- Fondazione Ricerca Fibrosi Cistica Onlus (FFC) [1/2014, 3/2017]
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.
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