Reviews in Computational Chemistry Volume 18

Critical Assessment of Current Scoring Functions 61
from these interactions to conventional interaction terms, which may be one
more reason why conventional hydrogen-bond contributions have traditionally
been overestimated. One could imagine adding terms to empirical scoring
functions that are omitted in the calibration of the functions, but adjusted
empirically to reward especially good fits, in a way analogous to penalty terms.
Knowledge-based methods would also allow one to incorporate these interactions
in a scoring function, again provided that directionality is taken into
account, which is not the case in current approaches.
Water Structure and Protonation State
Uncertainties about protonation states and water structure at the
receptor–ligand interface also make scoring difficult. These effects play a
role in the derivation as well as in the application of scoring functions. The
entropic and energetic contributions of water reorganization upon ligand
binding are very difficult to predict (see, e.g., Ref. 180). The only reasonable
approach for addressing this problem is to concentrate on conserved water
molecules and make them part of the receptor. For example, the docking program
FLOG has been applied to the search of inhibitors for a metallo-b-lactamase
13 within the Merck in-house database. Docking was performed with
three different configurations of bound water in the active site. The top-scoring
compounds showed an enrichment in biphenyl tetrazoles, several of which
were found to be active at a concentration below 20 mM. A crystal structure of
one tetrazole (IC50 ¼ 1.9 mM) not only confirmed the predicted binding mode
of one of the inhibitors, but also displayed the water configuration that had—
retrospectively—been the most predictive one of the three models.
Scoring functions rely on a fixed assignment of a general atom type to
each protein and ligand atom. This also implies a fixed assignment of protonation
state for each acidic and basic functional group. Even though these
assignments can be reliable enough for conditions in aqueous solution, significant
pKa shifts can be witnessed upon ligand binding. 181 This phenomenon
can arise from local changes of dielectric conditions inside the binding pocket.
The change of a donor to an acceptor functionality due to modified protonation
states has important consequences for scoring. 137 Accordingly, improved
docking and scoring algorithms will eventually need to have a more detailed
and flexible description of protonation states.
Performance in Structure Prediction
The multitude of different solutions that have been used for receptor–
ligand scoring calls for an objective assessment that could help future users
to decide which function to use under a given set of circumstances. To do this,
one must differentiate between predicting protein–ligand complex structures