Cy. Kim et al., Contribution of fluorine to protein-ligand affinity in the binding of fluoroaromatic inhibitors to carbonic anhydrase II, J AM CHEM S, 122(49), 2000, pp. 12125-12134
Carbonic anhydrase II (CAII) is a zinc metalloenzyme that catalyzes the hyd
ration of CO2 to yield bicarbonate and a proton. N-(4-Sulfamylbenzoyl)benzy
lamine (SBB) is a tight-binding inhibitor of human CAII with K-d = 2.1 nM.
Previous X-ray crystallographic work shows that the benzyl ring of SBB make
s an edge-to-face interaction with Phe-131 in the enzyme active site. We ha
ve manipulated the electrostatics of this interaction by systematically sub
stituting electronegative fluorine atoms for the benzyl ring hydrogens of S
BB. Crystal structures of 10 enzyme-inhibitor complexes have been determine
d to atomic resolution. Analysis of these structures reveals that the main
contributions to enzyme-inhibitor affinity can be approximated by a combina
tion of dipole-induced dipole, dipole-quadrupole, and quadrupole-quadrupole
interactions. Surprisingly, different electrostatic components dominate af
finity in different enzyme-inhibitor pairs.