Focused library design in GPCR projects on the example of 5‐HT2c agonists: Comparison of structure‐based virtual screening with ligand‐based search methods

Abstract

The aim of this study was to investigate the usefulness of structure-based virtual screening (VS) for focused library design in G protein-coupled receptors (GPCR) projects on the example of 5-HT(2c) agonists. We compared the performance of structure-based VS against two different homology models using FRED for docking and ScreenScore, FlexX, and PMF for rescoring with the results of 12 ligand-based similarity searches using four different query compounds and three different similarity metrics (Daylight, FTree, Phacir). The result of the similarity search showed much variation, from an enrichment factor up to 3.2 to worse than random, whereas the structure-based VS gave a more stable result with a constant enrichment factor around 2. Additionally, actives retrieved by the structure-based approach were more diverse than the actives among the top scorers of the similarity searches. Based on these results, we suggest basing a focused library design for a GPCR project on a combination of a ligand-based similarity search and structure-based docking.