Structural analysis of inhibitor binding to human carbonic anhydrase II.
Article Details
- CitationCopy to clipboard
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]
- Abstract
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
Drug Target Kind Organism Pharmacological Action Actions Brinzolamide Carbonic anhydrase 2 Protein Humans YesInhibitorDetails - Polypeptides
Name UniProt ID Carbonic anhydrase 2 P00918 Details - Binding Properties
Drug Target Property Measurement pH Temperature (°C) AL-4623 Carbonic anhydrase 2 Kd (nM) 0.32 7.4 37 Details AL5300 Carbonic anhydrase 2 Kd (nM) 0.2 7.4 37 Details AL5424 Carbonic anhydrase 2 Kd (nM) 0.16 7.4 37 Details AL5927 Carbonic anhydrase 2 Kd (nM) 0.49 7.4 37 Details AL6528 Carbonic anhydrase 2 Kd (nM) 0.13 7.4 37 Details AL7089A Carbonic anhydrase 2 Kd (nM) 0.1 7.4 37 Details AL7099A Carbonic anhydrase 2 Kd (nM) 1.7 7.4 37 Details AL7182 Carbonic anhydrase 2 Kd (nM) 0.1 7.4 37 Details Brinzolamide Carbonic anhydrase 2 Kd (nM) 0.13 7.4 37 Details N-(2-Thienylmethyl)-2,5-Thiophenedisulfonamide Carbonic anhydrase 2 Kd (nM) 0.83 7.4 37 Details THIOPHENE-2,5-DISULFONIC ACID 2-AMIDE-5-(4-METHYL-BENZYLAMIDE) Carbonic anhydrase 2 Kd (nM) 0.46 7.4 37 Details