Carbonic anhydrase inhibitors: X-ray crystallographic structure of the adduct of human isozyme II with EMATE, a dual inhibitor of carbonic anhydrases and steroid sulfatase

Bioorganic & Medicinal Chemistry Letters
2004.0

Abstract

The X-ray crystal structure for the adduct of human carbonic anhydrase II (hCA II) with estrone-3-O-sulfamate (EMATE), an antiendocrine agent showing both CA and estrone sulfatase inhibitory properties, has been resolved at a resolution of 1.5A. Its binding to the enzyme is similar to that of other sulfamates/sulfonamides, considering the interactions of the zinc anchoring group, but differs considerably when the steroidal scaffold of the inhibitor is analyzed. This part of the inhibitor interacts only within the hydrophobic half of the CA active site, interacting with residues Val 121, Phe 131, Val 135 and Pro 202, and leaving the hydrophilic half able to accommodate several water molecules not present in the uncomplexed enzyme. In addition, a very short bond of 1.78A between the zinc ion and the coordinated nitrogen atom of the sulfamate moiety is observed, which may explain the high affinity of this inhibitor for hCA II (K(i) of 10nM).

DOI： 10.1016/j.bmcl.2003.09.064

Knowledge Graph

Similar Paper

Carbonic anhydrase inhibitors: X-ray crystallographic structure of the adduct of human isozyme II with EMATE, a dual inhibitor of carbonic anhydrases and steroid sulfatase
Bioorganic & Medicinal Chemistry Letters 2004.0
Carbonic anhydrase inhibitors. Interaction of the antitumor sulfamate EMD 486019 with twelve mammalian carbonic anhydrase isoforms: Kinetic and X-ray crystallographic studies
Bioorganic & Medicinal Chemistry Letters 2008.0
Carbonic anhydrase inhibitors: Crystallographic and solution binding studies for the interaction of a boron-containing aromatic sulfamide with mammalian isoforms I–XV
Bioorganic & Medicinal Chemistry Letters 2010.0
Carbonic anhydrase inhibitors: X-ray crystallographic structure of the adduct of human isozyme II with the antipsychotic drug sulpiride
Bioorganic & Medicinal Chemistry Letters 2004.0
Carbonic anhydrase inhibitors. The X-ray crystal structure of human isoform II in adduct with an adamantyl analogue of acetazolamide resides in a less utilized binding pocket than most hydrophobic inhibitors
Bioorganic & Medicinal Chemistry Letters 2010.0
Docking studies of sulphamate inhibitors of estrone sulphatase in human carbonic anhydrase II
Bioorganic & Medicinal Chemistry Letters 2003.0
Carbonic Anhydrase Inhibitors:  Clash with Ala65 as a Means for Designing Inhibitors with Low Affinity for the Ubiquitous Isozyme II, Exemplified by the Crystal Structure of the Topiramate Sulfamide Analogue
Journal of Medicinal Chemistry 2006.0
Carbonic Anhydrase Inhibitors. Inhibition of Cytosolic Isozymes I and II and Transmembrane, Tumor-Associated Isozyme IX with Sulfamates Including EMATE Also Acting as Steroid Sulfatase Inhibitors
Journal of Medicinal Chemistry 2003.0
Carbonic anhydrase inhibitors: SAR and X-ray crystallographic study for the interaction of sugar sulfamates/sulfamides with isozymes I, II and IV
Bioorganic & Medicinal Chemistry Letters 2003.0
Carbonic anhydrase inhibitors: Inhibition of human, bacterial, and archaeal isozymes with benzene-1,3-disulfonamides—Solution and crystallographic studies
Bioorganic & Medicinal Chemistry Letters 2007.0