Analysis of structure-based virtual screening studies and characterization of identified active compounds

Abstract

Structure-based virtual screening makes explicit or implicit use of 3D target structure information to detect novel active compounds. Results of nearly 300 currently available original applications have been analyzed to characterize the state-of-the-art in this field. Compound selection from docking calculations is much influenced by subjective criteria. Although submicromolar compounds are identified, the majority of docking hits are only weakly potent. However, only a small percentage of docking hits can be reproduced by ligand-based methods. When docking calculations identify potent hits, they often originate from specialized compound sources (e.g., pharmaceutical compound decks or target-focused libraries) and also display a notable bias towards kinase targets. Structure-based virtual screening is the dominant approach to computational hit identification. Docking calculations frequently identify active compounds. Limited accuracy of compound scoring and ranking currently presents a major caveat of the approach that is often compensated for by chemical intuition and knowledge.