Expanding FTMap for Fragment-Based Identification of Pharmacophore Regions in Ligand Binding Sites

The
knowledge of ligand binding hot spots and of the important
interactions within such hot spots is crucial for the design of lead
compounds in the early stages of structure-based drug discovery. The
computational solvent mapping server FTMap can reliably identify binding
hot spots as consensus clusters, free energy minima that bind a variety
of organic probe molecules. However, in its current implementation,
FTMap provides limited information on regions within the hot spots
that tend to interact with specific pharmacophoric features of potential
ligands. E-FTMap is a new server that expands on the original FTMap
protocol. E-FTMap uses 119 organic probes, rather than the 16 in the
original FTMap, to exhaustively map binding sites, and identifies
pharmacophore features as atomic consensus sites where similar chemical
groups bind. We validate E-FTMap against a set of 109 experimentally
derived structures of fragment–lead pairs, finding that highly
ranked pharmacophore features overlap with the corresponding atoms
in both fragments and lead compounds. Additionally, comparisons of
mapping results to ensembles of bound ligands reveal that pharmacophores
generated with E-FTMap tend to sample highly conserved protein–ligand
interactions. E-FTMap is available as a web server at https://eftmap.bu.edu.