R. Wolfenden, ARE THERE LIMITS TO ENZYME-INHIBITOR BINDING-DISCRIMINATION - INFERENCES FROM THE BEHAVIOR OF NUCLEOSIDE DEAMINASES, Pharmacology & therapeutics, 60(2), 1993, pp. 235-244
An enzyme can enhance the rate of a reaction only to the extent that i
t binds the altered substrate in the transition state (S-not equal) mo
re tightly than it binds the substrate in the ground state. Inhibitors
that resemble S-not equal can be used to stop an enzyme from working,
probe its mechanism of action and obtain exact structural information
about intermediates in catalysis. In S-not equal analog inhibitors of
adenosine and cytidine deaminases, a single hydroxyl group appears to
make extremely large contributions to binding affinity. The magnitude
of this contribution becomes even more striking when differences in f
ree energy of solvation by water are taken into account. Other results
, obtained by deleting individual binding determinants, indicate the o
peration of remarkable levels of cooperativity and suggest that if eve
ry group is in exactly the right position and is part of an inflexible
structure, then a single substituent or H-bond can produce very large
increases in binding affinity. Some implications for inhibitor design
are considered.