Benchmark Sets for Binding Hot Spot Identification in Fragment-Based Ligand Discovery

Binding
hot spots are regions of proteins that, due to their potentially
high contribution to the binding free energy, have high propensity
to bind small molecules. We present benchmark sets for testing computational
methods for the identification of binding hot spots with emphasis
on fragment-based ligand discovery. Each protein structure in the
set binds a fragment, which is extended into larger ligands in other
structures without substantial change in its binding mode. Structures
of the same proteins without any bound ligand are also collected to
form an unbound benchmark. We also discuss a set developed by Astex
Pharmaceuticals for the validation of hot and warm spots for fragment
binding. The set is based on the assumption that a fragment that occurs
in diverse ligands in the same subpocket identifies a binding hot
spot. Since this set includes only ligand-bound proteins, we added
a set with unbound structures. All four sets were tested using FTMap,
a computational analogue of fragment screening experiments to form
a baseline for testing other prediction methods, and differences among
the sets are discussed.