Reviews in Computational Chemistry Volume 18

structures are peptidic in nature, whereas interesting lead molecules in
pharmaceutical research are usually nonpeptidic. This influence of peptides
is reflected in the relatively high contributions of hydrogen bonds in the total
score. The balance between hydrogen bonding and hydrophobic interactions is
a critical issue in scoring, and its consequences are especially obvious in virtual
screening applications, as will be illustrated in the later section on Hydrogen
Bonding versus Hydrophobic Interactions.
Molecular Size
Critical Assessment of Current Scoring Functions 59
The simple additive nature of most fast scoring functions often leads to
large molecules being assigned high scores. Although it is true that small molecules
with a molecular weight below 200–250 are rarely of very high affinity,
there is no guarantee that larger compounds are more active. When it comes to
comparing scores of two compounds of different size, it therefore makes sense
to include a penalty term that diminishes the dependence of the score on molecular
size. In some applications, a constant penalty value has been added to the
score for each heavy atom. 167 Alternatively, a penalty term proportional to the
molecular weight has been used. 168 The scoring function of the docking program
FLOG, which contains force field and empirical terms, has been normalized
to remove the linear dependence of the crude score on the number of
ligand atoms that was found in a docking study of a 7500 compound database.
59 Entropy terms designed to estimate the restriction of conformational
mobility upon ligand binding also help to eliminate overly large and flexible
molecules, although they were originally introduced to improve the correlation
between experimental and calculated affinities. 56,71 The size of the
solvent-accessible surface of the ligand within the protein-binding pocket is
also a useful penalty term because it helps avoid excessively large ligands
that cannot fit completely into the binding site. Note, however, that all these
approaches are very pragmatic in nature and do not solve the problem of size
dependence, which is closely linked to the understanding of cooperativity
effects. 125
Other Penalty Terms
Scoring functions in general reward certain favorable interactions such
as hydrogen bonds, but rarely penalize unfavorable interactions. Since scoring
functions are derived from experimentally determined crystal structures,
‘‘unnatural’’ and energetically unfavorable orientations of a ligand within
the receptor cavity are rarely observed and therefore cannot be accounted
for by the scoring function. Knowledge-based scoring functions try to capture
such effects indirectly by making those interactions repulsive that are not
observed in crystal structures. It seems, however, that the statistical difference