Contribution of Fluorine to Protein−Ligand Affinity in the Binding of Fluoroaromatic Inhibitors to Carbonic Anhydrase II
Citations Over TimeTop 16% of 2000 papers
Abstract
Carbonic anhydrase II (CAII) is a zinc metalloenzyme that catalyzes the hydration of CO2 to yield bicarbonate and a proton. N-(4-Sulfamylbenzoyl)benzylamine (SBB) is a tight-binding inhibitor of human CAII with Kd = 2.1 nM. Previous X-ray crystallographic work shows that the benzyl ring of SBB makes an edge-to-face interaction with Phe-131 in the enzyme active site. We have manipulated the electrostatics of this interaction by systematically substituting electronegative fluorine atoms for the benzyl ring hydrogens of SBB. Crystal structures of 10 enzyme−inhibitor complexes have been determined to atomic resolution. Analysis of these structures reveals that the main contributions to enzyme−inhibitor affinity can be approximated by a combination of dipole−induced dipole, dipole−quadrupole, and quadrupole−quadrupole interactions. Surprisingly, different electrostatic components dominate affinity in different enzyme−inhibitor pairs.
Related Papers
- → Structure determination of murine mitochondrial carbonic anhydrase V at 2.45-A resolution: implications for catalytic proton transfer and inhibitor design.(1995)100 cited
- → Human carbonic anhydrase inhibitory profile of mono- and bis-sulfonamides synthesized via a direct sulfochlorination of 3- and 4-(hetero)arylisoxazol-5-amine scaffolds(2017)26 cited
- → Benzimidazo[1,2-c][1,2,3]thiadiazole-7-sulfonamides as inhibitors of carbonic anhydrase(2007)25 cited
- → Selective recognition of carbonic anhydrase using transition metal complexes(2000)8 cited