title: Structure-based drug discovery of carbonic anhydrase inhibitors.
abstract: Inhibition of the metalloenzyme carbonic anhydrase (CA; EC 4.2.1.1) has pharmacologic applications in the field of anti-glaucoma, anti-convulsant and anti-cancer agents. But recently, it has also emerged that these enzymes have the potential for designing anti-infective drugs (anti-fungal and anti-bacterial agents) with a novel mechanism of action. Sulphonamides and their isosteres (sulphamates/sulphamides) constitute the main class of CA inhibitors (CAIs), which bind to the metal ion from the enzyme active site. Recently, the dithiocarbamates (DTCs), possessing a similar mechanism of action, were reported as a new class of inhibitors. These types of CAIs will be discussed in detail in this review. Novel drug design strategies have been reported ultimately based on the tail approach for obtaining sulphonamides/DTCs, which exploit more external binding regions within the enzyme active site (in addition to coordination to the metal ion), leading thus to isoform-selective compounds. Most of the promising data have been obtained by combining x-ray crystallography of enzyme-inhibitor adducts with novel synthetic approaches for generating chemical diversity. Whereas sulphonamide - NO donating hybrid drugs were reported as effective anti-glaucoma agents, most of the interesting new inhibitors were designed for inhibiting specifically the tumour-associated isoforms CA IX and XII, validated targets for imaging and treatment of hypoxic tumours. Promising compounds that inhibit CAs from bacterial and fungal pathogens, of the DTC and carboxylate types, will be also reviewed.
authors.affiliation: Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Via della Lastruccia, Sesto Fiorentino, Florence, Italy. claudiu.supuran@unifi.it
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects / Q000254:growth & development; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D005658:Fungi / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D013859:Thiocarbamates / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D002257:Carbonic Anhydrase Inhibitors; D005656:Fungal Proteins; D007527:Isoenzymes; D013449:Sulfonamides; D013859:Thiocarbamates; D002256:Carbonic Anhydrases