Let’s have a quick look at shape and isomerism.
In order for drugs to fit an active site,
they must first have the correct shape. And
we made reference to this earlier on.
Remember what I said about, for example, the
planar nature of aromatic rings. Sometimes
a planar shape is absolutely essential to
correctly bind to a lipophilic pocket within
a given receptor or enzyme. Usually, only
one isomer of a drug will have the required
activity. And by that, I don’t just necessarily
mean optical isomers. Most natural products,
however, do have stereocentres and occur in
a single optical isomer, otherwise known as
an enantiomer... enantiomer.
For example, we have the amino-acid which
make up proteins and hence, receptors and
enzymes. However, drugs should be administered
as single enantiomers as the mirror images
may have other effects including producing
side effects, which are unwanted, countering
the effects of the drug, which is something
that you actually see, for example, in the
antidepressant, citalopram, where it is administered
as a racemate. One enantiomer of the drug,
the S or sinister enantiomer, has been shown
to have a pronounced effect in the treatment
of depression. However, the R enantiomer has
actually been shown to counteract the effect
of the S.
Also, there is always a risk that one of the
drugs or one of the enantiomers can be metabolised
to a toxic product because the enzymes involved
in metabolism are also quite specific about
the types of things they break down and the
way in which certain drugs are converted into
So, let’s look at thalidomide, just briefly,
as an example.
Developed in the 1950s as a sedative and was
found... and was used as an over-the-counter
to treat nausea in pregnancy. However, it
was found that the drug caused devastating
abnormalities to the children of mothers taking
thalidomide, the most common being the limb
So, looking at the structures, you can see
that they are, to all intents and purposes,
well, identical. They contain the same number
of carbons, the same number of electrons,
the same number of hydrogens, oxygens and
nitrogens. However, investigation at the time
showed that it was the S, or sinister, enantiomer
that causes the sedation whereas the R, or
rectus, isomer causes birth defects. So, that
on the left, was responsible for the limb
malformation that was observed.
In the case of thalidomide, formulation of
the S isomer alone, however, was not sufficient
to remove the danger. And this is because
the drug can racemise in the body. And this
is facilitated by a biological process in
which epimerisation of that stereogenic centre
occurs. And you get conversion of the S to
the R. So, unfortunately, even in this particular
scenario, administering one particular enantiomer
would not have overcome the effects that were
observed, in terms of the negative effects,
as a teratogen.
Thalidomide, however, has made a reappearance
as it’s now being used against leprosy and
as an anti-cancer drug. So, bearing in mind,
it was prescribed for pregnant mothers and
therefore, this would have been an issue,
but for other members of society who would
be suffering, for example, from leprosy or
certain types of cancer, thalidomide still
has a role to play.
Now, I just want to briefly touch upon geometrical
You were made aware of this earlier on when
we were talking about alkenes in Module III
when we looked at the idea of cis- and trans-.
And this type of isomerism, just to recap,
is where you, being unable to rotate around
a double bond, get two groups which are the
same on either one side, such as in the case
of maleic acid shown on the left, which is
cis- and fumaric acid, which is trans, where
two groups are on either of that double bond.
There is no free rotation around a double
bond under normal conditions. It is, however,
possible to induce the rotation by applying
light of a certain frequency which, if you’re
really interested in finding out more, I recommend
you look at the photo-isomerism of stilbene.
The functional groups in this case essentially
end up in different places and you’ll see
it referred to either as cis- or zusammen
or z and trans- or entgegen or e.
And, finally, conformational isomerism. So,
remember what I said before about the idea
of fitting particular molecules because of
their shape into a particular cleft.
And this is cyclohexane. You can see its idealised,
regular hexagon structure, but the reality
is it exists either as the boat or as the
chair. So the chair structure, which is the
preferred structure, maximises the distance
between hydrogen atoms and carbon atoms, therefore,
reducing the degree of steric interaction
between different electron clouds within those
The problem when you’re thinking about this
though is, if you have a narrow cleft through
which only a planar molecule can fit, because
this is actually a kinked hexagon and not
a regular hexagon, this would render this
interaction of higher energy rather than a
lower energy interaction, which is what you
want to achieve.
If the drug has a preferred confirmation which
fits the active site then it will usually
bind more easily than if it is needed to adopt
an alternative shape.