Docking Performance of Fragments and Druglike Compounds

This paper addresses two questions of key interest to researchers working with protein–ligand docking methods: (i) Why is there such a large variation in docking performance between different test sets reported in the literature? (ii) Are fragments more difficult to dock than druglike compounds? To answer these, we construct a test set of in-house X-ray structures of protein–ligand complexes from drug discovery projects, half of which contain fragment ligands, the other half druglike ligands. We find that a key factor affecting docking performance is ligand efficiency (LE). High LE compounds are significantly easier to dock than low LE compounds, which we believe could explain the differences observed between test sets reported in the literature. There is no significant difference in docking performance between fragments and druglike compounds, but the reasons why dockings fail appear to be different.