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Protein Sci. Dec 1998; 7(12): 2483–2489.
PMCID: PMC2143894

Structural analysis of inhibitor binding to human carbonic anhydrase II.


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.

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Selected References

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  • Baldwin JJ, Ponticello GS, Anderson PS, Christy ME, Murcko MA, Randall WC, Schwam H, Sugrue MF, Springer JP, Gautheron P, et al. Thienothiopyran-2-sulfonamides: novel topically active carbonic anhydrase inhibitors for the treatment of glaucoma. J Med Chem. 1989 Dec;32(12):2510–2513. [PubMed]
  • BECKER B. Decrease in intraocular pressure in man by a carbonic anhydrase inhibitor, diamox; a preliminary report. Am J Ophthalmol. 1954 Jan;37(1):13–15. [PubMed]
  • Boriack PA, Christianson DW, Kingery-Wood J, Whitesides GM. Secondary interactions significantly removed from the sulfonamide binding pocket of carbonic anhydrase II influence inhibitor binding constants. J Med Chem. 1995 Jun 23;38(13):2286–2291. [PubMed]
  • Brünger AT, Kuriyan J, Karplus M. Crystallographic R factor refinement by molecular dynamics. Science. 1987 Jan 23;235(4787):458–460. [PubMed]
  • Burley SK, Petsko GA. Weakly polar interactions in proteins. Adv Protein Chem. 1988;39:125–189. [PubMed]
  • Chen RF, Kernohan JC. Combination of bovine carbonic anhydrase with a fluorescent sulfonamide. J Biol Chem. 1967 Dec 25;242(24):5813–5823. [PubMed]
  • Greer J, Erickson JW, Baldwin JJ, Varney MD. Application of the three-dimensional structures of protein target molecules in structure-based drug design. J Med Chem. 1994 Apr 15;37(8):1035–1054. [PubMed]
  • Håkansson K, Carlsson M, Svensson LA, Liljas A. Structure of native and apo carbonic anhydrase II and structure of some of its anion-ligand complexes. J Mol Biol. 1992 Oct 20;227(4):1192–1204. [PubMed]
  • Håkansson K, Liljas A. The structure of a complex between carbonic anhydrase II and a new inhibitor, trifluoromethane sulphonamide. FEBS Lett. 1994 Aug 22;350(2-3):319–322. [PubMed]
  • Jain A, Whitesides GM, Alexander RS, Christianson DW. Identification of two hydrophobic patches in the active-site cavity of human carbonic anhydrase II by solution-phase and solid-state studies and their use in the development of tight-binding inhibitors. J Med Chem. 1994 Jun 24;37(13):2100–2105. [PubMed]
  • KINSEY VE. Comparative chemistry of aqueous humor in posterior and anterior chambers of rabbit eye, its physiologic significance. AMA Arch Ophthalmol. 1953 Oct;50(4):401–417. [PubMed]
  • Ponticello GS, Freedman MB, Habecker CN, Lyle PA, Schwam H, Varga SL, Christy ME, Randall WC, Baldwin JJ. Thienothiopyran-2-sulfonamides: a novel class of water-soluble carbonic anhydrase inhibitors. J Med Chem. 1987 Apr;30(4):591–597. [PubMed]
  • Prugh JD, Hartman GD, Mallorga PJ, McKeever BM, Michelson SR, Murcko MA, Schwam H, Smith RL, Sondey JM, Springer JP, et al. New isomeric classes of topically active ocular hypotensive carbonic anhydrase inhibitors: 5-substituted thieno[2,3-b]thiophene-2-sulfonamides and 5-substituted thieno[3,2-b]thiophene-2-sulfonamides. J Med Chem. 1991 Jun;34(6):1805–1818. [PubMed]
  • Smith GM, Alexander RS, Christianson DW, McKeever BM, Ponticello GS, Springer JP, Randall WC, Baldwin JJ, Habecker CN. Positions of His-64 and a bound water in human carbonic anhydrase II upon binding three structurally related inhibitors. Protein Sci. 1994 Jan;3(1):118–125. [PMC free article] [PubMed]
  • Stams T, Chen Y, Boriack-Sjodin PA, Hurt JD, Liao J, May JA, Dean T, Laipis P, Silverman DN, Christianson DW. Structures of murine carbonic anhydrase IV and human carbonic anhydrase II complexed with brinzolamide: molecular basis of isozyme-drug discrimination. Protein Sci. 1998 Mar;7(3):556–563. [PMC free article] [PubMed]

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