Now, let’s quickly have a look at ion-dipole
bonds. Many drugs, sorry, many drug molecules
will be... have ionised functional groups.
Now, why you say? Because if we’re looking,
for example, at things like amines and carboxylic
acids, we already know that they have the
potential to either gain a proton or lose
And we also showed in the previous module
about amino-acids and their pI idea, indeed,
at what pH they are zwitterionic or
mostly negatively charged or mostly positively
charged. And this relates to this as well
because if you look at a secondary amine and
you were to put it into water at physiological
pH, you’d find that a good portion of that
would exist as its ammonium salt.
And this means that you’ve now got a positive
charge formerly on a nitrogen. And here you
can see in the diagram, we have here a phenylethylamine
shown here or phenylethylammonium salt interacting
its ion with the delta negative of the oxygen
or water. And this type of bonding plays a
key role in the water solubility of a drug.
Question: a salt of weak base in a weak acid
is not necessarily very water soluble. Why
And now, let’s just have a quick recap about
ionic bonding. Obviously in Module II, we
actually discussed this in considerable depth.
However, in the context of drug-receptor interactions,
it’s important to make sure you’re clear
Ionic bonds are formed between species that
have opposite charges, as you can see here,
where we have a carboxylate anion interacting
in an ionic fashion with a ammonium cation.
And it’s possible for these forces to act
over long distances. Indeed, the force between
two electrostatic charges falls off as a proportion
of 1/r2. Drugs are often ionised and the active
sites in receptors contain charge groups such
as carboxylic acids, for example, in the case
of a glutamic-acid amino-acid, and also lysine,
in the case of the amine-containing amino-acid.
So, that brings us onto the final type of
bonding, covalent bonding, which you should
already be familiar with in terms of the concept
back from Module I.
The majority of the bonds within drugs and
their targets will be covalent. And a small
number of the drugs can also make covalent
bonds with their targets.
I used the example of aspirin, salicylic acid,
making a covalent bond with COX-1,
Covalent bonds are strong and hence, drugs
forming them will usually be permanently bound
to their target unless, of course, a further
reaction to cleave that covalent bond takes
As you’ll see in the next slide, some anti-cancer
drugs alkylate DNA in tumour cells. These
are drugs such as chlorambucil and other mustard-based
drugs. The alkylated DNA cannot function and
hence, the cell dies. An example of this would
be mechlorethamine, which is shown on the
So, here we have a methyl-based mustard. The
reason it’s called this is from the original
origins of mustard gas in fairness. If we
look here at the structure, you can see that
we have a chloroethylamine type of structure.
So, here, we have a chloro group and an ethyl
group which is bound to a nitrogen group.
And it’s indeed the reactivity of this that
makes it most useful in terms of DNA, but
also highly toxic to everything else. And
hence, it’s used as a weapon of war.
So, let’s, for example, have a look at what’s
Remember what we said about the lone pair
on the nitrogen. The lone pair on the nitrogen
is very nucleophilic. And we know that, under
normal circumstances, it can react with a
molecule of haloalkane and then form a second
alkylated version of itself.
Now, what happens in this scenario is that
an intramolecular reaction occurs. The lone
pair of the nitrogen attacks the delta positive
on the chloroethyl group, kicks off the chloride.
But, of course, it doesn’t have a hydrogen
to lose because, as you can see, that amine
is a tertiary amine. There are no further
hydrogens to be lost as H+. And so, what you
end up with is a positively-charged species
shown in the right hand side known as an aziridinium
ring... aziridinium ring.
And what happens in this scenario is that
the rather nucleophilic part of one of the
bases in DNA such as, for example, the nitrogen
7 on guanine actually can attack this aziridinium
ring and open it up. What this results in
is a covalently-linked piece of DNA to our
mustard, our mechlorethamine. And this is
known as alkylation. So, whenever we are forming
a covalent bond between a heteroatom and an
alkyl group, this is also termed alkylation.
Now, if you can imagine what I showed you
before in terms of DNA and its strands and
how the bases were held together, they’re
held together by hydrogen bonds. But, the
idea behind that is that, when, for example,
DNA needs to be transcribed and that mRNA
needs to be translated, of course, the DNA
must unzip. If, as you can see here, it is
possible to covalently link two sets of bases
together from opposite strands, it means that
the DNA can itself not unzip and therefore,
you cannot get transcription. Thus, in the
case of, for example, cancer cells, where
cancer is... results in the rapid division
of cells as a consequence of the rapid replication
of DNA, this type of drug actually stops that
from happening, thus leading to cell death
because the DNA itself becomes non-viable.
Now, let’s bring on the role of water.