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

Citations Over TimeTop 10% of 2005 papers

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.

Related Papers

• → Carbonic anhydrase inhibitors: Thioxolone versus sulfonamides for obtaining isozyme-selective inhibitors?(2008)37 cited
• → Synthesis and investigation of inhibition effects of new carbonic anhydrase inhibitors(1997)23 cited
• → Thienothiopyransulfonamides as Complexing Agents for thePreparation of Dual Carbonic Anhydrase Inhibitors(1995)14 cited
• → The carbon dioxide hydration activity of purified teleost red cell carbonic anhydrase. Inhibition by sulfonamides and anions(1982)12 cited
• Carbonic anhydrase: a multigene-multifunctional enzyme.(1997)