Hybrid methods that rely on structural and ligand similarity were also developed to overcome the limitations of traditional VLS approaches. This methodologies utilizes evolution‐based ligand‐binding information to predict small-molecule binders and can employ both global structural similarity and pocket similarity. A global structural similarity based approach employs both an experimental structure or a predicted protein model to find structural similarity with proteins in the PDB holo‐template library. Upon detecting significant structural similarity, 2D fingerprint based Tanimoto coefficient metric is applied to screen for small-molecules that are similar to ligands extracted from selected holo PDB templates. The predictions from this method have been experimentally assessed  and shows good enrichment in identifying active small molecules.
The above specified method depends on global structural similarity and is not capable of a priori selecting a particular ligand‐binding site in the protein of interest. Further, since the methods rely on 2D similarity assessment for ligands, they are not capable of recognizing stereochemical similarity of small-molecules that are substantially different but demonstrate geometric shape similarity. To address these concerns, a new pocket centric approach, PoLi, capable of targeting specific binding pockets in holo‐protein templates, was developed and experimentally assessed.