6533b85afe1ef96bd12b98c2
RESEARCH PRODUCT
Exploring the readthrough of nonsense mutations by non-acidic Ataluren analogues selected by ligand-based virtual screening
Raffaella MelfiMarco TutoneAndrea PaceAldo Di LeonardoLaura LentiniIvana Pibirisubject
0301 basic medicineNonsense mutationDrug Evaluation PreclinicalMolecular ConformationCystic Fibrosis Transmembrane Conductance RegulatorMolecular Dynamics SimulationOxadiazolemedicine.disease_causeCftr geneCFTR gene03 medical and health scienceschemistry.chemical_compoundDrug DiscoverymedicineHumansRNA MessengerPharmacologyGeneticsOxadiazolesMessenger RNAVirtual screeningMutationNonsense mutationChemistryDrug Discovery3003 Pharmaceutical ScienceOrganic ChemistryGeneral MedicineLigand (biochemistry)PTCs readthroughMolecular biologyStop codonAtaluren030104 developmental biologyCodon NonsenseCystic fibrosiHeLa Cellsdescription
Abstract Ataluren, also known as PTC124, is a 5-(fluorophenyl)-1,2,4-oxadiazolyl-benzoic acid suggested to suppress nonsense mutations by readthrough of premature stop codons in the mRNA. Potential interaction of PTC124 with mRNA has been recently studied by molecular dynamics simulations highlighting the importance of H-bonding and stacking π−π interactions. A series of non-acidic analogues of PTC124 were selected from a large database via a ligand-based virtual screening approach. Eight of them were synthesized and tested for their readthrough activity using the Fluc reporter harboring the UGA premature stop codon. The most active compound was further tested for suppression of the UGA nonsense mutation in the bronchial epithelial IB3.1 cell line carrying the W1282X mutation in the CFTR gene.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2016-03-23 | European Journal of Medicinal Chemistry |