then these can be halted by the interference
with their enzymes.
Enzymes are generally targeted by inhibitors
which prevent them from working. These are
molecules which combine in the enzyme and
prevent substrates or cofactors from binding,
as we will see in the final slide for this
particular final lecture, for this particular
module, where we will be looking at penicillin-binding
protein, which is an example of an enzyme
found on the surface of bacteria which we
can target with antibiotics.
The reaction which the enzyme would normally
catalyse can then not take place. So, how
would you go about designing an enzyme inhibitor?
Give it some thought based on your understanding
of functional group and also shape and size.
Let’s have a look at how we can inhibit an
enzyme, stopping it from working. And I’d
like to draw your attention to the concept
of reversible inhibition. It’s been found
that some enzyme inhibitors block the active
site by binding in a similar way to the substrate,
that is to say, at the active site.
So, let’s have a look at two scenarios, where
we have our normal substrate, shown as the
blue ellipse binding to the enzyme, which
will then function. As you can appreciate,
if we have an inhibitor, which has a similar
affinity for the enzyme, there will be an
equilibrium between bound and unbound substrate
and bound and unbound inhibitor.
What this effectively means is if we increase
the concentration of the inhibitor, we stand
a better chance of inhibiting or blocking
the activity of the natural substrate at the
But, there will still be a competition for
that site with the substrate. Let’s have a
look and see what that means in more detail.
The enzyme itself will effectively be prevented
from working when the concentration of the
inhibitor is greater than the concentration
of the substrate.
And as you can see from the bottom, when we
have an excess of substrate, a reaction, the
normal reaction of an enzyme would do whatever
it would normally do can proceed unhindered.
In the presence of an excess of inhibitor,
however, the reaction does not proceed or
rather the rate of the reaction is substantially
reduced because most of the active sites of
the enzyme are blocked.
At lower concentrations of inhibitors, some
enzyme molecules will be inhibited and some
will be binding the substrate and the enzyme
activity will, therefore, be reduced. Inhibitors
that work in this way are described as reversible
Now, let’s have a look in a bit more detail
about the alternative. These are also called
irreversible inhibitors. Some inhibitors will
bind to an enzyme permanently by making a
And if you go back to what we were talking
about, right at the beginning, regarding bio-chemical
interactions as part of Module IV, we discussed
all the possible intermolecular forces that
are at work: van der Waals forces, dipole-dipole,
ion-dipole and so forth.
And all of these are generally found when
you are looking at the characteristics of
a reversible inhibitor where the energy required
to overcome those intermolecular interactions
is not so great.
But, when we are talking about irreversible
inhibition, what we are effectively talking
about is covalent bonding. When we are talking
about covalent bonding, we are forming very
strong bonds between the enzyme and whichever
our drug happens to be and whatever our inhibitor
happens to be.
And it’s often very difficult to remove them
once they are in place. The inhibitor inhibition
cannot be overcome by increasing the concentration
of the natural substrate, in this case, because
as the name suggests, the active site is irreversibly
And there are couple of good examples of this,
as we will see a little later on. There is
the example of aspirin which covalently binds
to cycloxygenase-1. There is also, for
example, organophosphates which bind irreversibly
to the acetylcholine esterase active
Indeed, in that scenario, what happens is
the actual three dimensional structure of the
enzyme fundamentally changes within about
half an hour, therefore, stopping the reversal
of that particular inhibition.
When there is irreversible inhibition, often
times what is necessary is that the enzyme
itself isn’t broken down by the host’s natural
systems and then reconstituted again. This
Generally, irreversible inhibition comes on
quickly as soon as the concentration of the
inhibitor near the enzyme rises. Irreversible
inhibition may take time to come on as a...
may take time for the covalent bonds to form.
So, now, we have talked about reversible and
irreversible. Let’s look at competitive and
non-competitive inhibition. So, the example
of reversible inhibition, described previously,
can also be described as a type of competitive
inhibition; competitive because, of course,
we are competing with the substrate itself.
The substrate and inhibitor molecules ultimately
compete for the same binding site.
The example of irreversible inhibition is
an example of a non-competitive inhibition
since once the inhibitor binds, it stays put
and the substrate itself cannot then compete
The inhibitor studied so far talk about binding
in the active site and this is where you get
the competition or where you have bounded
selectively and irreversibly where you see
a lack of competition.
But now, I’d like to talk to you a little
bit about something called allosteric inhibition.
So, where you have got binding, which doesn’t
take place at the active site, then maybe
at a site a distance away from it, these binding
sites can be known as allosteric sites.
Inhibitors which bind at these allosteric
sites ultimately change the shape of the enzyme,
but don’t directly influence the active site
itself. However, as we will see, this can
ultimately prevent substrates binding at the