Polyamines inhibit carbonic anhydrases by anchoring to the zinc-coordinated water molecule.
Article Details
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Carta F, Temperini C, Innocenti A, Scozzafava A, Kaila K, Supuran CT
Polyamines inhibit carbonic anhydrases by anchoring to the zinc-coordinated water molecule.
J Med Chem. 2010 Aug 12;53(15):5511-22. doi: 10.1021/jm1003667.
- PubMed ID
- 20590092 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Acetazolamide Carbonic anhydrase 1 Ki (nM) 250 N/A N/A Details Acetazolamide Carbonic anhydrase 12 Ki (nM) 5.7 N/A N/A Details Acetazolamide Carbonic anhydrase 14 Ki (nM) 41 N/A N/A Details Acetazolamide Carbonic anhydrase 2 Ki (nM) 12 N/A N/A Details Acetazolamide Carbonic anhydrase 3 Ki (nM) 200000 N/A N/A Details Acetazolamide Carbonic anhydrase 4 Ki (nM) 74 N/A N/A Details Acetazolamide Carbonic anhydrase 7 Ki (nM) 2.5 N/A N/A Details Diclofenamide Carbonic anhydrase 1 Ki (nM) 1200 N/A N/A Details Diclofenamide Carbonic anhydrase 2 Ki (nM) 38 N/A N/A Details Diclofenamide Carbonic anhydrase 3 Ki (nM) 680000 N/A N/A Details Diclofenamide Carbonic anhydrase 4 Ki (nM) 15000 N/A N/A Details Diclofenamide Carbonic anhydrase 7 Ki (nM) 26 N/A N/A Details