title: Carbonic anhydrase inhibitors: stacking with Phe131 determines active site binding region of inhibitors as exemplified by the X-ray crystal structure of a membrane-impermeant antitumor sulfonamide complexed with isozyme II.
abstract: Structure for the adduct of carbonic anhydrase II with 1-N-(4-sulfamoylphenyl-ethyl)-2,4,6-trimethylpyridinium perchlorate, a membrane-impermeant antitumor sulfonamide, is reported. The phenylethyl moiety fills the active site, making van der Waals interactions with side chains of Gln192, Val121, Phe131, Leu198, Thr200. The 2,4,6-trimethylpyridinium functionality is at van der Waals distance from the aliphatic chain of Ile91 being involved in strong offset face-to-face stacking with Phe131. Analyzing X-ray crystal structures of such adducts, two binding modes were observed: some inhibitors bind with their tail within the hydrophobic half of the active site, defined by residues Phe131, Val135, Leu198, Pro202, Leu204. Other derivatives bind with their tail in a different region, pointing toward the hydrophilic half and making strong parallel stacking with Phe131. This interaction orients the inhibitor toward the hydrophilic part of the active site. Impossibility to participate in it leads to its binding within the hydrophobic half. Such findings are relevant for designing better inhibitors targeting isozymes II, IX, and XII, some of which are overexpressed in hypoxic tumors.
authors.affiliation: Istituto di Biostrutture e Bioimmagini-CNR, via Mezzocannone 16, 80134 Naples, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Menchise
authors.forename: Giuseppina
authors.initials: G
authors.lastname: De Simone
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Alterio
authors.forename: Anna
authors.initials: A
authors.lastname: Di Fiore
authors.forename: Carlo
authors.initials: C
authors.lastname: Pedone
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000951:Antigens, Neoplasm / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000737:chemistry; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000737:chemistry; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011726:Pyridinium Compounds / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013449:Sulfonamides / Q000737:chemistry*
chemical_list: C504985:1-N-(4-sulfamoylphenylethyl)-2,4,6-trimethylpyridinium; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007527:Isoenzymes; D011726:Pyridinium Compounds; D011994:Recombinant Proteins; D013449:Sulfonamides; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases