Structure-based screening for the discovery of new carbonic anhydrase VII inhibitors

•A 3D pharmacophore model has been generated for carbonic anhydrase VII inhibitors.•A virtual screening workflow was set up to find new carbonic anhydrase VII inhibitors.•Selected compounds were subjected to docking studies.•Two hits were identified with nanomolar Ki values towards hCA VII isoform.

Among the different mammalian isoforms of Carbonic Anhydrase, the hCA VII is mainly expressed in the brain where it is involved in several neurological diseases. Thereby hCA VII has been validated as an attractive target for the discovery of selective inhibitors for the treatment of epilepsy and neurological pain. To identify new chemical entities as carbonic anhydrase inhibitors (CAIs) targeting hCA VII, we used a structure-based approach. By means of LigandScout software we built pharmacophore models from crystal structures of two well-known CAIs in complex with hCA VII. A merged pharmacophore hypothesis has been obtained. Subsequently, a focused library of compounds was screened against pharmacophore model and the most interesting hits were docked into the crystal structure of hCA VII. As a result, we identified new compounds displaying significant CA inhibitory effects in the nanomolar range.

Graphical abstractA merged structure-based pharmacophore model has been generated that led to the discovery of highly potent new carbonic anhydrase VII inhibitors.Figure optionsDownload full-size imageDownload as PowerPoint slide