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

Abstract

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 ₁AR) and docked ∼2.2 M lead-like compounds. High-ranking molecules were tested on the A ₁AR as well as the close homologs A _2AAR and A ₃AR. 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.