Polyamines Inhibit Carbonic Anhydrases by Anchoring to the Zinc-Coordinated Water Molecule

被引：180

作者：

Carta, Fabrizio ^{[1
]}

Temperini, Claudia ^{[1
]}

Innocenti, Alessio ^{[1
]}

Scozzafava, Andrea ^{[1
]}

Kaila, Kai ^{[2
,3
]}

Supuran, Claudiu T. ^{[1
]}

机构：

[1] Univ Florence, Chim Bioorgan Lab, I-50019 Sesto Fiorentino, Florence, Italy

[2] Univ Helsinki, Dept Biosci, Helsinki 000140, Finland

[3] Univ Helsinki, Ctr Neurosci, Helsinki 000140, Finland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 15期

基金：

芬兰科学院;

关键词：

ISOZYME-IV ACTIVATORS; ACTIVE-SITE; CRYSTAL-STRUCTURE; ISOFORM-VII; CRYSTALLOGRAPHIC ANALYSIS; L-HISTIDINE; ALZHEIMERS; PROTEINS; DESIGN; BRAIN;

D O I：

10.1021/jm1003667

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Carbonic anhydrases (CAs, EC 4.2.1.1) are inhibited by sulfonamides, phenols, and coumarins. Polyamines such as spermine, spermidine, and many synthetic congeners are described to constitute a novel class of CA inhibitors (CAIs), interacting with the different CA isozymes with efficiency from the low nanomolar to millimolar range. The main structure activity relationship for these CAIs have been delineated: the length of the molecule, number of amine moieties, and their functionalization are the main parameters controlling activity. The X-ray crystal structure of the CA II spermine adduct allowed understanding of the inhibition mechanism. Spermine anchors to the nonprotein zinc ligand through a network of hydrogen bonds. Its distal amine moiety makes hydrogen bonds with residues Thr200 and Pro201, which further stabilize the adduct. Spermine binds differently compared to sulfonamides, phenols, or coumarins, rendering possible to develop CAIs with a diverse inhibition mechanism, profile, and selectivity for various isoforms.

引用

页码：5511 / 5522

页数：12

共 56 条

[1]

ALTERIO V, 2010, BIOORG MED CHEM LETT, V20, P3467

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