I want to spend a few minutes
talking about a different view
of druggability, a different way
of thinking about the relationship
between the structure of approaching
surface and its potential
to bind small molecule ligand.
This concept relates to
proposition 4, the proposition
that the druggability of a
protein/protein interaction target
can usefully be thought of as
its potential ligand deficiency.
The idea of ligand
deficiency goes back
to a seminal paper published
by Kuntz et al in 1999.
In this study, the authors
analyzed a large number of ligands
for proteins for which there were
reliable affinity values reported
in the literature.
And what they showed-- as
illustrated on the figure shown
here, which I took from that paper--
is that the amount of binding
energy that a ligand can
generate with its target
correlates with the
size of the ligand,
as quantified here in terms of the
number of heavy atoms, the number
of non-hydrogen atoms
in the ligand structure.
And you can see that this
relationship appears to saturate.
But at the lower extreme shown
by the solid line in the figure,
you can see that for each additional
heavy atom of ligand structure,
and additional up to 1.5
kilocalories per mole
of binding energy can be generated.
That corresponds to an
increase in binding affinity
of more than tenfold
for the addition
of each additional heavy
atom of ligand structure.
The relationship between
the size of a ligand
and the amount of binding
energy it can generate
is quantified with a view to
its utility for drug discovery
by Hopkins and Groom in
2004, and substantially
extended by Phil Hajduk from the
Abbott group a few years later.
And the bottom line here is that
if you imagine a typical drug has
a molecular weight less
than 500 atomic mass units,
and typically will have a binding
affinity of at least 10 nanomolar
in order to be
this corresponds then to about
0.3 kilocalories per mole
of binding energy
generated per heavy atom,
per non-hydrogen atom present
in that drug structure.
And this ratio of binding
energy to ligand heavy atoms
is known as the ligand efficiency.
The higher that number is, the
more binding energy the ligand
is generating for its size, and
therefore the more efficiently it
is extracting binding energy from
its interaction with the protein,
and the more strongly it will bind.