Accurate Binding Free Energy Predictions in Fragment Optimization

Predicting protein–ligand
binding free energies is a central
aim of computational structure-based drug design (SBDD)  improved
accuracy in binding free energy predictions could significantly reduce
costs and accelerate project timelines in lead discovery and optimization.
The recent development and validation of advanced free energy calculation
methods represents a major step toward this goal. Accurately predicting
the relative binding free energy changes of modifications to ligands
is especially valuable in the field of fragment-based drug design,
since fragment screens tend to deliver initial hits of low binding
affinity that require multiple rounds of synthesis to gain the requisite
potency for a project. In this study, we show that a free energy perturbation
protocol, FEP+, which was previously validated on drug-like lead compounds,
is suitable for the calculation of relative binding strengths of fragment-sized
compounds as well. We study several pharmaceutically relevant targets
with a total of more than 90 fragments and find that the FEP+ methodology,
which uses explicit solvent molecular dynamics and physics-based scoring
with no parameters adjusted, can accurately predict relative fragment
binding affinities. The calculations afford R2-values on average greater than 0.5 compared to experimental
data and RMS errors of ca. 1.1 kcal/mol overall, demonstrating significant
improvements over the docking and MM-GBSA methods tested in this work
and indicating that FEP+ has the requisite predictive power to impact
fragment-based affinity optimization projects.