Reviews in Computational Chemistry Volume 18

48 The Use of Scoring Functions in Drug Discovery Applications
studied. From X-ray studies, it was known that the side chain hydroxyl of Tyr
82 forms a hydrogen bond with the ligand. If Tyr 82 is replaced by Phe, then
one hydrogen bond is lost. As expected, the ligand-binding affinity was slightly
reduced. The free enthalpy difference is 4 1:5 kJ/mol. Somewhat unexpectedly,
however, this destabilization is due to an entropy loss. In other words,
the formation of this particular hydrogen bond is enthalpically unfavorable
but entropically favorable. The entropy gain appears to be mainly due to
the replacement of two water molecules by the ligand. 41
Lipophilic interactions are essentially contacts between apolar parts
of the protein and the ligand. The generally accepted view is that lipophilic
interactions are mainly the result of the replacement and release of ordered
water molecules and thus are entropy-driven processes. 42,43 The entropy
gain is due to the fact that the water molecules are no longer positionally confined.
There are also enthalpic contributions to lipophilic interactions. Water
molecules occupying lipophilic binding sites are unable to form hydrogen
bonds with the protein. If they are released, they can form strong hydrogen
bonds with bulk water. It has been shown in many cases that the lipophilic
contribution to the binding affinity is proportional to the lipophilic surface
area buried from the solvent and typically has values in the range of 80–
200 J/(mol A ˚ 2 ). 44–46
Conformational flexibility is another factor influencing the binding affinity.
Usually, a ligand binds in a single conformation and therefore loses much
of its conformational flexibility upon binding. Greater binding affinities have
been observed for cyclic derivatives of ligands that otherwise adopt the same
binding mode. 47,48 The entropic cost of freezing a single rotatable bond has
been estimated to be 1.6–3.6 kJ/mol at 300 K. 49,50 Recent estimates derived
from nuclear magnetic resonance (NMR) shift titrations of open-chain dications
and dianions are much lower (0.5 kJ/mol), 51 but in those systems the conformational
restriction may not have been as high as in a protein-binding site.
The entropic cost of the external (translational and orientational) degrees of
freedom has been estimated to be around 10 kJ/mol. 52,53
In spite of many inconsistencies and difficulties in interpretation, most of
the experimental data suggests that simple additive models for the protein–
ligand interactions might be a good starting point for the development of
empirical scoring functions. Indeed, the first published scoring functions
were actually built based on experimental work that was published by about
1992, including studies on thermolysin 54 and vancomycin. 50,55
Figure 3 summarizes some of the interactions that play a role in receptor–
ligand binding. Binding involves a complex equilibrium between ensembles of
solvated species. In the next section, we will discuss various approaches that
are used to capture essential elements of this equilibrium in computationally
efficient scoring functions. The discussion focuses on general approaches
rather than individual functions. The reader is referred to Table 1 for original
references to the most important scoring functions. 56–114