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Focused library design in GPCR projects on the example of 5‐HT 2c agonists: Comparison of structure‐based virtual screening with ligand‐based search methods
Author(s) -
Bissantz Caterina,
Schalon Claire,
Guba Wolfgang,
Stahl Martin
Publication year - 2005
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.20651
Subject(s) - virtual screening , structural similarity , docking (animal) , g protein coupled receptor , similarity (geometry) , computational biology , computer science , homology modeling , drug discovery , chemistry , artificial intelligence , bioinformatics , biology , receptor , biochemistry , medicine , nursing , image (mathematics) , enzyme
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. Proteins 2005. © 2005 Wiley‐Liss, Inc.