A computer-assisted discovery of novel potential anti-obesity compounds as selective carbonic anhydrase VA inhibitors

European Journal of Medicinal Chemistry
Giosuè CostaClaudiu T Supuran

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.

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Citations

May 10, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Annalisa MarucaStefano Alcaro
Mar 17, 2020·Expert Opinion on Drug Metabolism & Toxicology·Claudiu T Supuran
Dec 2, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Annalisa MarucaAnna Artese
Dec 4, 2020·International Journal of Molecular Sciences·Annalisa MarucaStefano Alcaro
May 21, 2021·Clinical Science·Claudiu T Supuran
Sep 7, 2021·Journal of Enzyme Inhibition and Medicinal Chemistry·Alessio NocentiniClemente Capasso

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