Identification of New Carbonic Anhydrase VII Inhibitors by Structure-Based Virtual Screening

GANTNER, MELISA E.; PRADA GORI, DENIS N.; LLANOS, MANUEL A.; TALEVI, ALAN; ANGELI, ANDREA; VULLO, DANIELA; SUPURAN, CLAUDIU T.; GAVERNET, LUCIANA

JOURNAL OF CHEMICAL INFORMATION AND MODELING

AMER CHEMICAL SOC

Año: 2022 vol. 62 p. 4760 - 4770

1549-9596

Human carbonic anhydrase VII (hCA VII) constitutes a promising molecular target for the treatment of epileptic seizures and other central nervous system disorders due to its almost exclusive expression in neurons. Achieving isoform selectivity is one of the main challenges for the discovery of new hCA inhibitors, since nonspecific inhibition may lead to tolerance and side effects. In the present work, we report the development of a molecular docking protocol based on AutoDock4Znfor the search of new hCA VII inhibitors by virtual screening. The docking protocol was applied to the screening of two sets of compounds: a ZINC15 subset of sulfur-containing structures and an in-house library consisting of synthetic and commercial candidates (including approved drugs). Five compounds were selected from the first screening campaign and three from the second one, and they were tested in vitro against the enzyme. Among the eight selected structures, four showed Kivalues in the low nanomolar range. These confirmed hits include three approved drugs: meloxicam, piroxicam, and nitrofurantoin, which also showed good selectivity for hCA VII versus hCA II.