Structural analysis of inhibitor binding to human carbonic anhydrase II.

Article Details


Boriack-Sjodin PA, Zeitlin S, Chen HH, Crenshaw L, Gross S, Dantanarayana A, Delgado P, May JA, Dean T, Christianson DW

Structural analysis of inhibitor binding to human carbonic anhydrase II.

Protein Sci. 1998 Dec;7(12):2483-9.

PubMed ID
9865942 [ View in PubMed

X-ray crystal structures of carbonic anhydrase II (CAII) complexed with sulfonamide inhibitors illuminate the structural determinants of high affinity binding in the nanomolar regime. The primary binding interaction is the coordination of a primary sulfonamide group to the active site zinc ion. Secondary interactions fine-tune tight binding in regions of the active site cavity >5 A away from zinc, and this work highlights three such features: (1) advantageous conformational restraints of a bicyclic thienothiazene-6-sulfonamide-1,1-dioxide inhibitor skeleton in comparison with a monocyclic 2,5-thiophenedisulfonamide skeleton; (2) optimal substituents attached to a secondary sulfonamide group targeted to interact with hydrophobic patches defined by Phe131, Leu198, and Pro202; and (3) optimal stereochemistry and configuration at the C-4 position of bicyclic thienothiazene-6-sulfonamides; the C-4 substituent can interact with His64, the catalytic proton shuttle. Structure-activity relationships rationalize affinity trends observed during the development of brinzolamide (Azopt), the newest carbonic anhydrase inhibitor approved for the treatment of glaucoma.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
BrinzolamideCarbonic anhydrase 2ProteinHumans
NameUniProt ID
Carbonic anhydrase 2P00918Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
AL-4623Carbonic anhydrase 2Kd (nM)0.327.437Details
AL5300Carbonic anhydrase 2Kd (nM)0.27.437Details
AL5424Carbonic anhydrase 2Kd (nM)0.167.437Details
AL5927Carbonic anhydrase 2Kd (nM)0.497.437Details
AL6528Carbonic anhydrase 2Kd (nM)0.137.437Details
AL7089ACarbonic anhydrase 2Kd (nM)0.17.437Details
AL7099ACarbonic anhydrase 2Kd (nM)1.77.437Details
AL7182Carbonic anhydrase 2Kd (nM)0.17.437Details
BrinzolamideCarbonic anhydrase 2Kd (nM)0.137.437Details
N-(2-Thienylmethyl)-2,5-ThiophenedisulfonamideCarbonic anhydrase 2Kd (nM)0.837.437Details
THIOPHENE-2,5-DISULFONIC ACID 2-AMIDE-5-(4-METHYL-BENZYLAMIDE)Carbonic anhydrase 2Kd (nM)0.467.437Details