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

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‐HT2c 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.

[1]  Alan Wise,et al.  Target validation of G-protein coupled receptors. , 2002, Drug discovery today.

[2]  D. Rognan,et al.  Protein-based virtual screening of chemical databases. 1. Evaluation of different docking/scoring combinations. , 2000, Journal of medicinal chemistry.

[3]  M Rarey,et al.  Detailed analysis of scoring functions for virtual screening. , 2001, Journal of medicinal chemistry.

[4]  J. Thompson,et al.  CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. , 1994, Nucleic acids research.

[5]  K. Palczewski,et al.  Crystal Structure of Rhodopsin: A G‐Protein‐Coupled Receptor , 2002, Chembiochem : a European journal of chemical biology.

[6]  Caterina Bissantz,et al.  5-HT 2C Receptor Agonists for the Treatment of Obesity. Biological and Chemical Adventures , 2004 .

[7]  J. Ballesteros,et al.  Beta2 adrenergic receptor activation. Modulation of the proline kink in transmembrane 6 by a rotamer toggle switch. , 2002, The Journal of biological chemistry.

[8]  J. Baldwin,et al.  An alpha-carbon template for the transmembrane helices in the rhodopsin family of G-protein-coupled receptors. , 1997, Journal of molecular biology.

[9]  Lei Shi,et al.  The second extracellular loop of the dopamine D2 receptor lines the binding-site crevice. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Darko Butina,et al.  Unsupervised Data Base Clustering Based on Daylight's Fingerprint and Tanimoto Similarity: A Fast and Automated Way To Cluster Small and Large Data Sets , 1999, J. Chem. Inf. Comput. Sci..

[11]  Thomas Lengauer,et al.  A fast flexible docking method using an incremental construction algorithm. , 1996, Journal of molecular biology.

[12]  T. Schwartz,et al.  Locating ligand-binding sites in 7TM receptors by protein engineering. , 1994, Current opinion in biotechnology.

[13]  L. F. Kolakowski,et al.  Novel GPCRs and their endogenous ligands: expanding the boundaries of physiology and pharmacology. , 1999, Trends in pharmacological sciences.

[14]  Didier Rognan,et al.  Protein‐based virtual screening of chemical databases. II. Are homology models of g‐protein coupled receptors suitable targets? , 2002, Proteins.

[15]  G. V. Paolini,et al.  Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes , 1997, J. Comput. Aided Mol. Des..

[16]  J Hoflack,et al.  The Binding Site of Neuropeptide Vasopressin V1a Receptor , 1995, The Journal of Biological Chemistry.

[17]  Y. Martin,et al.  A general and fast scoring function for protein-ligand interactions: a simplified potential approach. , 1999, Journal of medicinal chemistry.

[18]  J. Baldwin.  The probable arrangement of the helices in G protein‐coupled receptors. , 1993, The EMBO journal.

[19]  Gerhard Klebe,et al.  Ligand-supported homology modeling of g-protein-coupled receptor sites: models sufficient for successful virtual screening. , 2004, Angewandte Chemie.

[20]  Matthias Rarey,et al.  Feature trees: A new molecular similarity measure based on tree matching , 1998, J. Comput. Aided Mol. Des..

[21]  J Hoflack,et al.  Three-dimensional models of neurotransmitter G-binding protein-coupled receptors. , 1991, Molecular pharmacology.

[22]  R. Henderson,et al.  Model for the structure of bacteriorhodopsin based on high-resolution electron cryo-microscopy. , 1990, Journal of molecular biology.

[23]  C. Humblet,et al.  G-Protein coupled receptors: models, mutagenesis, and drug design. , 1998, Journal of medicinal chemistry.

[24]  S. Henikoff,et al.  Amino acid substitution matrices from protein blocks. , 1992, Proceedings of the National Academy of Sciences of the United States of America.