HAMMERHEAD - FAST, FULLY AUTOMATED DOCKING OF FLEXIBLE LIGANDS TO PROTEIN-BINDING SITES

Background: Molecular docking seeks to predict the geometry and affini ty of the binding of a small molecule to a given protein of known stru cture. Rigid docking has long been used to screen databases of small m olecules, because docking techniques that account for ligand flexibili ty have either been too slow or have required significant human interv ention, Here we describe a docking algorithm, Hammerhead, which is a f ast, automated tool to screen for the binding of flexible molecules to protein binding sites. Results: We used Hammerhead to successfully do ck a variety of positive control ligands into their cognate proteins. The empirically tuned scoring function of the algorithm predicted bind ing affinities within 1.3 log units of the known affinities for these ligands, Conformations and alignments close to those determined crysta llographically received the highest scores. We screened 80 000 compoun ds for binding to streptavidin, and biotin was predicted as the top-sc oring ligand, with other known ligands included among the highest-scor ing dockings, The screen ran in a few days on commonly available hardw are. Conclusions: Hammerhead is suitable for screening large databases of flexible molecules for binding to a protein of known structure. It correctly docks a variety of known flexible ligands, and it spends an average of only a few seconds on each compound during a screen. The a pproach is completely automated, from the elucidation of protein bindi ng sites, through the docking of molecules, to the final selection of compounds for assay.