Rapid and Reliable Binding Affinity Prediction of Bromodomain Inhibitors: A Computational Study

Binding
free energies of bromodomain inhibitors are calculated
with recently formulated approaches, namely ESMACS (enhanced sampling
of molecular dynamics with approximation of continuum solvent) and
TIES (thermodynamic integration with enhanced sampling). A set of
compounds is provided by GlaxoSmithKline, which represents a range
of chemical functionality and binding affinities. The predicted binding
free energies exhibit a good Spearman correlation of 0.78 with the
experimental data from the 3-trajectory ESMACS, and an excellent correlation
of 0.92 from the TIES approach where applicable. Given access to suitable
high end computing resources and a high degree of automation, we can
compute individual binding affinities in a few hours with precisions
no greater than 0.2 kcal/mol for TIES, and no larger than 0.34 and
1.71 kcal/mol for the 1- and 3-trajectory ESMACS approaches.