Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects

Accurate
ranking of compounds with regards to their binding affinity
to a protein using computational methods is of great interest to pharmaceutical
research. Physics-based free energy calculations are regarded as the
most rigorous way to estimate binding affinity. In recent years, many
retrospective studies carried out both in academia and industry have
demonstrated its potential. Here, we present the results of large-scale prospective application of the FEP+ method in active drug
discovery projects in an industry setting at Merck KGaA, Darmstadt,
Germany. We compare these prospective data to results obtained on
a new diverse, public benchmark of eight pharmaceutically relevant
targets. Our results offer insights into the challenges faced when
using free energy calculations in real-life drug discovery projects
and identify limitations that could be tackled by future method development.
The new public data set we provide to the community can support further
method development and comparative benchmarking of free energy calculations.