Transition State Analogues and Adventitious Tight-binding Inhibitors

2 Transition State Analogues and Adventitious Tight-binding Inhibitors 

The idea of transition state binding has proved very fruitful in understanding enzymic catalysis in general, as researchers have looked for specific transition state interactions between enzyme and substrate. To the author, though, the frequently encountered statement that enzymes work by binding transition states , without elaboration, is a tautology - as we have seen, the concept of transition state binding follows immediately from elementary transition state theory. 

If enzymes bind transition states more tightly than substrates, then they should bind molecules which resemble transition states in shape and/or charge more tightly than they bind substrates or products. The concept of transition state analogue was first applied to glycosyl transfer by Leaback, who 

Therefore, as was understood 20 years ago, there are three types of interaction which can be exploited in designing glycosidase inhibitors similarity to the shape of the transition state, similarity to the charge distribution of the transition state and salt bridge/hydrogen bonding interactions with catalytic carboxylates.  

The binding of two iminoalditol inhibitors showed bell-shaped profiles, with the acid limb corresponding to the acid dissociation of the enzyme (constant K-s) and the basic limb to the deprotonation the inhibitor, acid dissociation constant Ki [eqn. (5.27)]. 

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