CorrEA: A Web Server for Optimizing Correlations between Calculated Energies and Activities in Ligand–Receptor Systems Considering Multiple Binding Site Conformations

In silico molecular models of receptor–ligand
complexes, built using molecular docking methods, are valuable as
they potentially reveal the chemical interactions responsible for
specific affinities. When applied to series of congeneric compounds,
they help formulate theories about the effects of different substituents
on affinity differences. Molecular docking provides (i) a pose where
chemical interactions are optimized and (ii) an energy value indicating
how favorable the interaction is. The capability of molecular docking
for the first purpose is recognized, but it fails considerably in
the second. It is widely known that energy values obtained by molecular
docking are unreliable, which makes their application to congeneric
series unable to correlate these computationally calculated energy
values with laboratory-derived biological activities. Theoretically,
an improved correlation could be obtained when protein flexibility
is considered in the docking calculation; i.e., flexibility in the
protein residues at the binding site can give access to more representative
docking solutions. With this in mind, in this work, we present the
novel web server CorrEA with a simple and innovative way of considering
the flexibility of ligand–protein systems. To apply the method,
users must generate a set of receptor conformations exhibiting significant
variability within the binding site. Subsequently, they should cross-dock
the ligand series they intend to study, to obtain various poses for
each ligand across the different receptor conformations. CorrEA performs
a genetic algorithm (GA) selection to extract a representative complex
for each ligand that better adjusts the global correlation between
calculated docking energy values and experimental logarithmic biological
activities. In the end, CorrEA provides the ligand–protein
pairs that produce the highest correlations. The new method was tested
in several different cases to demonstrate its usefulness.