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

Abstract

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 AutoDock4Zn for 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 K i values 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.

MM/GBSA prediction of relative binding affinities of carbonic anhydrase inhibitors: effect of atomic charges and comparison with Autodock4Zn

“…In the context of CA inhibitor design, molecular docking has been widely used to screen ligands against a variety of isoforms [ 17 , 27 , 30 , 38 ]. Recently, a docking protocol was used to screen a library of compounds against CA VII and identified four ligands with low nanomolar potency [ 23 ]. However, the predictive power of docking methods for screening hCA ligands was limited until a scoring function (Autodock4 Zn ) was optimised to better describe the interactions between the ligand and the Zn(II) centre [ 64 ].…”