| Literature DB >> 31387062 |
Giosuè Costa1, Fabrizio Carta2, Francesca Alessandra Ambrosio3, Anna Artese4, Francesco Ortuso1, Federica Moraca5, Roberta Rocca6, Isabella Romeo7, Antonio Lupia1, Annalisa Maruca1, Donatella Bagetta1, Raffaella Catalano1, Daniela Vullo2, Stefano Alcaro1, Claudiu T Supuran2.
Abstract
The human Carbonic anhydrases (hCA) VA and VB play a key role in ureagenesis, gluconeogenesis, lipogenesis and in the metabolism regulation, thus representing highly popular drug targets. Albeit several hCA inhibitors have been designed and are currently in clinical use, serious drug interactions have been reported due to their poor selectivity. In this perspective, the drug repurposing approach could be a useful tool in order to investigate the drug promiscuity/polypharmacology profile. In this study, virtual screening techniques and in vitro assays were combined to identify novel selective hCA VA inhibitors from among around 94000 compounds. The docking analysis highlighted 12 promising best hits, biologically characterized in terms of their hCA VA inhibitory activity. Interestingly, among them, the anticancer agents fludarabine and lenvatinib and the antiepileptic rufinamide were able to selectively inhibit the enzyme activity in the micromolar range, while a pyrido-indole derivative, the homovanillic acid sulfate and the desacetyl metabolite of the antibacterial cephapirin in the nanomolar range.Entities:
Keywords: Carbonic anhydrase; Drug repurposing; Isoform-selective inhibitors; Obesity; Virtual screening
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Year: 2019 PMID： 31387062 DOI： 10.1016/j.ejmech.2019.111565
Source DB: PubMed Journal: Eur J Med Chem ISSN： 0223-5234 Impact factor: 6.514