Computational Methodologies for Compound Database Searching that Utilize Experimental Protein–Ligand Interaction Information

Ligand- and target structure-based methods are widely used in virtual screening, but there is currently no methodology available that fully integrates these different approaches. Herein, we provide an overview of various attempts that have been made to combine ligand- and structure-based computational screening methods. We then review different types of approaches that utilize protein-ligand interaction information for database screening and filtering. Interaction-based approaches make use of a variety of methodological concepts including pharmacophore modeling and direct or indirect encoding of protein-ligand interactions in fingerprint formats. These interaction-based methods have been successfully applied to tackle different tasks related to virtual screening including postprocessing of docking poses, prioritization of binding modes, selectivity analysis, or similarity searching. Furthermore, we discuss the recently developed interacting fragment approach that indirectly incorporates 3D interaction information into 2D similarity searching and bridges between ligand- and structure-based methods.