Assessment of Binding Affinity via Alchemical Free-Energy Calculations

Free-energy calculations
have seen increased usage in structure-based
drug design. Despite the rising interest, automation of the complex
calculations and subsequent analysis of their results are still hampered
by the restricted choice of available tools. In this work, an application
for automated setup and processing of free-energy calculations is
presented. Several sanity checks for assessing the reliability of
the calculations were implemented, constituting a distinct advantage
over existing open-source tools. The underlying workflow is built
on top of the software Sire, SOMD, BioSimSpace, and OpenMM and uses
the AMBER 14SB and GAFF2.1 force fields. It was validated on two datasets
originally composed by Schrödinger, consisting of 14 protein
structures and 220 ligands. Predicted binding affinities were in good
agreement with experimental values. For the larger dataset, the average
correlation coefficient Rp was 0.70 ±
0.05 and average Kendall’s τ was 0.53 ± 0.05, which
are broadly comparable to or better than previously reported results
using other methods.