Structural Stability Predicts the Binding Mode of Protein–Ligand Complexes

The prediction of
a ligand’s binding mode into its macromolecular
target is essential in structure-based drug discovery. Even though
tremendous effort has been made to address this problem, most of the
developed tools work similarly, trying to predict the binding free
energy associated with each particular binding mode. In this study,
we decided to abandon this criterion, following structural stability
instead. This view, implemented in a novel computational workflow,
quantifies the steepness of the local energy minimum associated with
each potential binding mode. Surprisingly, the protocol outperforms
docking scoring functions in case of fragments (ligands with MW <
300 Da) and is as good as docking for drug-like molecules. It also
identifies substructures that act as structural anchors, predicting
their binding mode with particular accuracy. The results open a new
physical perspective for binding mode prediction, which can be combined
with existing thermodynamic-based approaches.