title: Structure-based screening for the discovery of new carbonic anhydrase VII inhibitors.
abstract: 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.
authors.affiliation: Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università di Messina, Viale Annunziata, I-98168 Messina, Italy. Electronic address: ldeluca@unime.it.
authors.forename: Laura
authors.initials: L
authors.lastname: De Luca
authors.affiliation: Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università di Messina, Viale Annunziata, I-98168 Messina, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Ferro
authors.affiliation: Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università di Messina, Viale Annunziata, I-98168 Messina, Italy.
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Damiano
authors.affiliation: Università degli Studi di Firenze, Dipartimento NEUROFARBA, Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: Università degli Studi di Firenze, Dipartimento NEUROFARBA, Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.affiliation: Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università di Messina, Viale Annunziata, I-98168 Messina, Italy.
authors.forename: Alba
authors.initials: A
authors.lastname: Chimirri
authors.affiliation: Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università di Messina, Viale Annunziata, I-98168 Messina, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Gitto
mesh_terms: D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; C477051:carbonic anhydrase VI
keywords: CAIs; CAs; Carbonic anhydrase; Docking; H; H-bond acceptors; H-bond donors; HBA; HBD; LigandScout; Structure-based pharmacophore model; Virtual screening; carbonic anhydrase inhibitors; carbonic anhydrases; hCA VII; hydrophobic group