00:01
Let’s have a quick look
at shape and isomerism.
00:05
In order for drugs to fit an active site,
they must first have the correct shape.
00:09
And we made reference
to this earlier on.
00:12
Remember what I said about, for example,
the planar nature of aromatic rings.
00:16
Sometimes a planar shape
is absolutely essential
to correctly bind to
a lipophilic pocket
within a given
receptor or enzyme.
00:25
Usually, only one isomer of a drug
will have the required activity.
00:29
And by that, I don’t just
necessarily mean optical isomers.
00:34
Most natural products,
however, do have stereocentres
and occur in a single
optical isomer,
otherwise known as an enantiomer,
enantiomer.
00:45
For example,
we have the amino-acid
which make up proteins
and hence,
receptors and enzymes.
00:53
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.
01:13
One enantiomer of the drug,
the S or sinister enantiomer,
has been shown to have
a pronounced effect in the
treatment of depression.
01:21
However, the R enantiomer has
actually been shown to counteract
the effect of the S.
01:28
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 metabolites.
01:48
So, let’s look at thalidomide,
just briefly, as an example.
01:53
Developed in the
1950's as a sedative
and was found and was used
as an over-the-counter
to treat nausea in pregnancy.
02:01
However,
it was found that the drug caused
devastating abnormalities to the
children of mothers taking thalidomide,
the most common being
the limb malformation.
02:12
So, looking at the structures, you can see
that they are, to all intents and purposes,
well, identical.
02:17
They contain the same number of
carbons, the same number of electrons,
the same number of hydrogens,
oxygens and nitrogens.
02:24
However,
investigation at the time
showed that it was the
R, or rectus,
enantiomer that
causes the sedation
whereas the S, or sinister,
isomer causes birth defects.
02:37
So, that on the right, was responsible for
the limb malformation that was observed.
02:42
In the case of thalidomide,
formulation of the R isomer
alone, however, was not sufficient
to remove the danger.
02:51
And this is because the drug
can racemise in the body.
02:55
And this is facilitated
by a biological process
in which epimerisation of that
stereogenic centre occurs.
03:03
And you get conversion
of the R to the S.
03:08
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.
03:22
Thalidomide, however,
has made a reappearance
as it’s now being used against
leprosy and as an anti-cancer drug.
03:30
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.
03:47
Now, I just want to briefly
touch upon geometrical isomerism.
03:51
We 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-.
04:01
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.
04:23
There is no free rotation
around a double bond
under normal conditions.
04:28
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.
04:43
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.
04:56
And, finally,
conformational isomerism.
04:59
So, remember what I said
before about the idea
of fitting particular molecules
because of their shape
into a particular cleft.
05:06
And this is cyclohexane.
05:08
You can see its idealised,
regular hexagon structure,
but the reality is it
exists either as the boat
or as the chair.
05:17
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 molecular orbitals.
05:31
The problem when you’re thinking about
this though is, if you have a narrow cleft
which only a planar
molecule can fit,
because this is actually a kinked hexagon
and not through a regular hexagon,
this would render this
interaction of higher energy
rather than a lower energy interaction,
which is what you want to achieve.
05:52
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.