Comparison of Structure- and Ligand-Based Virtual Screening Protocols Considering Hit List Complementarity and Enrichment Factors

摘要

Structure- and ligand-based virtual-screening methods (docking, 2D- and 3D-similarity searching) were analysed for their effectiveness in virtual screening against four different targets: angiotensin-converting enzyme (ACE), cyclooxygenase 2 (COX-2), thrombin and human immunodeficiency virus 1 (HIV-1) protease. The relative performance of the tools was compared by examining their ability to recognise known active compounds from a set of actives and nonactives. Furthermore, we investigated whether the application of different virtual-screening methods in parallel provides complementary or redundant hit lists. Docking was performed with GOLD, Glide, FlexX and Sur-flex. The obtained docking poses were rescored by using nine different scoring functions in addition to the scoring functions implemented as objective functions in the docking algorithms. Ligand-based virtual screening was done with ROCS (3D-simi-larity searching), Feature Trees and Scitegic Functional Fingerprints (2D-similarity searching). The results show that structure-and ligand-based virtual-screening methods provide comparable enrichments in detecting active compounds. Interestingly, the hit lists that are obtained from different virtual-screening methods are generally highly complementary. These results suggest that a parallel application of different structure- and ligand-based virtual-screening methods increases the chance of identifying more (and more diverse) active compounds from a virtual-screening campaign.