So, let’s have a look at an example. Here
we have our enzyme, shown in green, and we
have our substrate, shown in blue. Obviously,
under normal circumstances, binding would occur,
a reaction would occur and then the products
of that enzyme catalysed reaction would be
Here we have an example inhibitor, shown as
a red rectangle. Instead of directly attacking
the active site, which is what we have seen
in the past, this inhibitor is shown to be
antagonising a allosteric site.
Note how the shape of the active site is now
changed in our cartoon, gone from being the
same shape as the substrate or half of the
substrate to being substantially smaller.
The change in the shape of the active site
thus prevents the substrate from binding successfully
and prevents the reaction from taking place.
A good example of some of these would be in
the case of the non-nucleoside reverse
transcriptase inhibitors used in the treatment
of HIV, for example, nevirapine. Because the
inhibitor binds at the allosteric site, the
active site changes shape and the substrate
can no longer bind.
The inhibition, however, is reversible because
the inhibitor is not permanently bound at
the allosteric site and again, would be reliant
upon the type of intermolecular forces, which
we have discussed before: weak intermolecular
forces, dipole-dipole or ion-dipole, for example.
The binding is, therefore, an equilibrium,
as we saw when we were talking about reversible
inhibition. If the concentration of the inhibitor
drops, then the enzyme is less likely to be
bound to it and the enzyme activity will,
as a consequence, increase.
So, let’s have a look at irreversible enzyme.
And I was talking about salicylic acid and
aspirin earlier on. Aspirin in of itself is
actually a pro-drug for the active salicylic
acid shown here.
Remember what we said, pro-drugs are often
esters and here, you can see that we have
an ester group attached to a benzene ring,
attached to a carboxylic acid group. And in
this particular case, the aspirin ester group
is hydrolysed and salicylic acid is the result.
What I’d like you to do is to consider what
type of metabolic transformation converts
the aspirin to the salicylic acid and how
much you draw out the mechanism of that.
So, now, let’s quickly have a quick look at
the biological role of aspirin, since we have
discussed it. It’s so important. Irreversible
inhibition of cyclooxygenase-1 is responsible
for reducing the amount of arachidonic acid
derivative, PGG, which is part of the inflammatory
cascade found within, for example, the human
Cyclooxygenase, otherwise known as prostaglandins
synthase, is important in the body for the
biosynthesis of prostaglandins which are responsible
for pain and inflammation, as I have said.
In the middle of the screen, you can see one
of the precursors to these prostaglandins
known as arachidonic acid and what cyclooxygenase
does, as you can see, is it's responsible
for the catalytic oxidation of specific sides
around that arachidonic acid. By inhibiting
the action of this enzyme, you can reduce
the amount of prostaglandin, thus reducing
the inflammatory marker and reducing, therefore,
pain as a consequence.
Now we've discussed enzymes, we are now going
to be looking more at the pharmacodynamics
and pharmacokinetics and then after this,
we will be moving onto pro-drug design and
also a short example of beta-lactam antibiotics
and derivatives of those.