Limits of Ligand Selectivity from Docking to Models: In Silico Screening for A(1) Adenosine Receptor Antagonists

作者：Kolb Peter^*; Phan Khai; Gao Zhan Guo; Marko Adam C; Sali Andrej; Jacobson Kenneth A

来源：PLos One, 2012, 7(11): e49910.

DOI：10.1371/journal.pone.0049910

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 A(1) adenosine receptor (A(1)AR) and docked similar to 2.2 M lead-like compounds. High-ranking molecules were tested on the A(1)AR as well as the close homologs A(2A)AR and A(3)AR. 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.

• 出版日期2012-11-21