Hotspot guided evaluation of docked poses

Hotspots within the binding site afford a disproportionate contribution to the ligands’ binding energy. We have shown that hotspots, identified with FTMap server,1 have a better correlation to the compounds’ ligand efficiency (LE) than to their affinity.2 Verdonk and co-workers showed that compounds with high LE are easier to dock than compounds with low LE.3 Hence, ligands’ overlap to hotspots (FO) might be employed to analyze docking results. In order to investigate this hypothesis, we mapped the hotspots from 30 unique proteins that have at least 5 ligands each (408 PDBs) and then evaluated the ligands’ overlap to different ensembles of hotspots. This approach revealed that low LE compounds have significantly lower overlap to druggable compact/continuous ensembles of hotspots than high LE compounds. Next, we employed the ligands’ overlap to filter the results from cross-docking experiments.