Details

Autor(en) / Beteiligte

• Kolb, Peter
• Phan, Khai
• Gao, Zhan-Guo
• Marko, Adam C.
• Sali, Andrej
• Jacobson, Kenneth A.
• Seifert, Roland

Titel

Limits of Ligand Selectivity from Docking to Models: In Silico Screening for A1 Adenosine Receptor Antagonists

Ist Teil von

• PloS one, 2012-11, Vol.7 (11), p.e49910

Ort / Verlag

San Francisco: Public Library of Science

Erscheinungsjahr

2012

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• G protein-coupled receptors (GPCRs) are attractive targets for pharmaceutical research. With the recent determination of several GPCR X-ray structures, the applicability of structure-based computational methods for ligand identification, such as docking, has increased. Yet, as only about 1% of GPCRs have a known structure, receptor homology modeling remains necessary. In order to investigate the usability of homology models and the inherent selectivity of a particular model in relation to close homologs, we constructed multiple homology models for the A1 adenosine receptor (A1AR) and docked ∼2.2 M lead-like compounds. High-ranking molecules were tested on the A1AR as well as the close homologs A2AAR and A3AR. While the screen yielded numerous potent and novel ligands (hit rate 21% and highest affinity of 400 nM), it delivered few selective compounds. Moreover, most compounds appeared in the top ranks of only one model. These findings have implications for future screens.