title: Virtual screening-driven identification of human carbonic anhydrase inhibitors incorporating an original, new pharmacophore.
abstract: Combinated ligand- and pharmacophore-based virtual screening approaches were used to discover novel potential pharmacophores acting as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs). A free database of commercially available compounds was screened through drug-like filters using a four-point pharmacophore, and followed by docking calculation within the active site of an X-ray structure of isoform CA II. One compound, bearing a trifluoro-dihydroxy-propanone moiety, showed an interesting, selective inhibitory activity in low micromolar range against this isoform versus CA I. The chemical originality of this new pharmacophore can represent an important bioisosteric alternative to the sulfonamido-based functionalities, thus leading to the development of a new class of CAIs.
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Sassari, Via Muroni 23/A, 07100 Sassari, Italy.
authors.forename: Nicolino
authors.initials: N
authors.lastname: Pala
authors.forename: Roberto
authors.initials: R
authors.lastname: Dallocchio
authors.forename: Alessandro
authors.initials: A
authors.lastname: Dessì
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Carta
authors.forename: Simone
authors.initials: S
authors.lastname: Ihm
authors.forename: Alfonso
authors.initials: A
authors.lastname: Maresca
authors.forename: Mario
authors.initials: M
authors.lastname: Sechi
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors / Q000378:metabolism; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D003198:Computer Simulation; D016208:Databases, Factual; D006801:Humans; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II