Chemistry Reference
In-Depth Information
11.5 Using Ligand Efficiency for Hit Evaluation and Optimization
As discussed above, hits with low affinity but small molecular size may have advant-
ages over larger compounds with stronger affinity toward the successful optimization and
delivery of drug-like clinical candidates. Several scaling factors have been introduced to
assess the binding affinity within the context of ligand size and other properties.
[
37
]
These
include metrics based on polar surface area, molecular weight and number of heavy (non-
hydrogen) atoms. While each method has particular advantages, they all seek to provide
some measure of how much each atom in a small molecule contributes to a binding inter-
action with a macromolecule. Among these methods, we have found it useful to consider
a ligand's efficiency as the binding energy per heavy atom (with heavy atom defined as all
atoms except hydrogen).
[
38
]
In general, the free energy of binding (
G
) was not determ-
ined; instead, IC
50
values were used (Figure 11.6). Of course, molecular weight is highly
correlated with the heavy atom count; based on the analysis of 201 marketed CNS drugs
that are assumed to passively distribute into the brain, we find that on average each heavy
atom contributes about 14 Da to the molecular weight. [The correlation is MW
=
(14.051)
(heavy atom count)
0.9734. When considering all orally delivered drugs,
the mean molecular weight per heavy atom is only slightly higher, MW
+
0.3829,
R
2
=
=
(14.248) (heavy
atom count)
+
2.5452,
R
2
=
0.9429.]
G / HAC
LE = RT ln(K
d
)
/
HAC
LE ≈ RT ln(IC
50
)
/
HAC
LE ≈−0.592ln(IC
50
)
/
HAC
LE
=−
Figure 11.6
Expressions for ligand efficiency (LE). HAC
=
heavy atom count, K
=
298 K,
R
=
1.987
×
10
−3
kcal K
−1
mol
−1
.
To improve the likelihood of the successful delivery of orally bioavailable CNS drugs,
research programs will aim towards molecular weights of less than around 500 Da (
<
36
heavy atoms) and affinity/potency for the target of around 10 nM. In Figure 11.7, a com-
pound with these properties is represented by point A. Further increases in the potency or
decreases in molecular weight are both desirable and define the shaded region. The ligand
efficiency of the compound represented by point A is approximately 0.30. By fixing this
value as the target ligand efficiency, the correlation between affinity and heavy atom count
is shown as the middle line in Figure 11.7. Any compounds that reside to the left of this line
have higher ligand efficiency and can be considered to be tending toward desirable drug-like
features. Any compounds that reside to the right of the line have lower ligand efficiency and
may be considered to have atoms contributing to a smaller extent to the productive binding
interaction. Of course, the delivery of successful drug candidates requires balancing among
many properties. In this discussion of drug-likeness, ligand efficiency monitors only the
interaction of the ligand with its target and is therefore well suited for the evaluation of
early-stage compounds. Other chemical features will influence the optimization of physical
