期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 11, 期 5, 页码 747-753出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.9b00609
关键词
Pharmacophore modeling; cystic fibrosis; premature termination codons; nonsense mutation; HTVS
资金
- Fondazione Ricerca Fibrosi Cistica-Onlus (FFC), Italy grant FFC [3/2017]
- Delegazione di Palermo, Delegazione di Vittoria (Ragusa) e Siracusa
- Delegazione di Catania Mascalucia and Fondazione Terzo Pilastro International
Translational readthrough-inducing drugs (TRIDs ) rescue the functional full-length protein expression in genetic diseases, such as cystic fibrosis, caused by premature termination codons (PTCs). Small molecules have been developed as TRIDs to trick the ribosomal machinery during recognition of the PTC. Herein we report a computational study to identify new TRID scaffolds. A pharmacophore approach was carried out on compounds that showed readthrough activity. The pharmacophore model applied to screen different libraries containing more than 87000 compounds identified four hit-compounds presenting scaffolds with diversity from the oxadiazole lead. These compounds have been synthesized and tested using the Fluc reporter harboring the UGA PTC. Moreover, the cytotoxic effect and the expression of the CFTR protein were evaluated. These compounds, a benzimidazole derivative (NV2899), a benzoxazole derivative (NV2913), a thiazole derivative (NV2909), and a benzene-1,3-disulfonate derivative (NV2907), were shown to be potential new lead compounds as TRIDs, boosting further efforts to address the optimization of the chemical scaffolds.
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