Are predicted protein structures of any value for binding site prediction and virtual ligand screening?

The recently developed field of ligand homology modeling (LHM) that extends the ideas of protein homology modeling to the prediction of ligand binding sites and for use in virtual ligand screening has emerged as a powerful new approach. Unlike traditional docking methodologies, LHM can be applied to low-to-moderate resolution predicted as well as experimental structures with little if any diminution in performance; thereby enabling ∼75% of an average proteome to have potentially significant virtual screening predictions. In large scale benchmarking, LHM is able to predict off-target ligand binding. Thus, despite the widespread belief to the contrary, low-to-moderate resolution predicted structures have considerable utility for biochemical function prediction.

► Ligand homology modeling (LHM) can use low-to-moderate resolution models for binding site predictions and virtual screening. ► LHM performs better with protein models than traditional approaches do for crystal structures. ► LHM is applicable to ∼75% of an average proteome. ► LHM is a promising approach to repurpose FDA approved drugs.