usually bind to an enzyme by strong covalent bonds. However, in both revers-
ible and irreversible inhibition the inhibitor does not need to bind to the active
site in order to prevent enzyme action.
Reversible: EþIÐEI complex
Irreversible: EþI!EI complex
7. 3. 1 Reversible inhibitors
These are inhibitors that form a dynamic equilibrium system with the enzyme.
The inhibitory effects of reversible inhibitors are normally time dependent
because the removal of unbound inhibitor from the vicinity of its site of action
by natural processes will disturb this equilibrium to the left. As a result, more
enzyme becomes available, which causes a decrease in the inhibition of the
process catalysed by the enzyme. Consequently, reversible enzyme inhibitors
will only be effective for a specific period of time.
Most reversible inhibitors may be further classified as being eithercompeti-
tive, non-competitive oruncompetitive.Incompetitive inhibition the inhibitor
usuallybinds by a reversible process to the same active site of the enzyme as
the substrate. Since the substrate and inhibitor compete for the same active site
it follows that they will probably be structurally similar (Figure 7.3). This offers
a rational approach to drug design in this area.
COO− COO−COO−
SuccinateCOO−
FumarateCOO−COO−
MalonateSuccinate
dehydrogenaseFigure 7.3 The similarity of the structures of malonate and succinate explains why malonate
inhibits succinate dehydrogenase
Non-competitive inhibitorsbind reversibly to an allosteric site (see Appendix 7)
on the enzyme. Inpurenon-competitive inhibition, the binding of the inhibitor
to the enzyme does not influence the binding of the substrate to the enzyme.
However, this situation is uncommon, and the binding of the inhibitor usually
causes conformational changes in the structure of the enzyme, which in turn
affects the binding of the substrate to the enzyme. This is known asmixednon-
competitive inhibition. The fact that the inhibitor does not bind to the active site
of the enzyme means that the structure of the substrate cannot be used as the
basis of designing new drugs that act in this manner to inhibit enzyme action.
DRUGS THAT TARGET ENZYMES 139