G Protein-Coupled Receptors (GPCRs) are key players in the signal transduction across the cellular membrane, and currently constitute the main drug target class. Crystal structures of GPCRs have recently revealed the molecular basis of ligand binding and receptor activation. Molecular docking screens using these structures have achieved high hit rates, and provided the discovery of novel and potent ligands for different receptors of pharmaceutically relevance. Moreover, the ligands discovered typically matched the activation profile of the co-crystallographic ligand, suggesting that an efficacy bias was encoded in GPCR crystal structures. The A2A adenosine receptor (A2AAR) has received a considerable attention from the pharmaceutical industry, and A2AAR antagonists are in clinical trials for the treatment of several CNS disorders. However, the potential of the A2AAR as a therapeutic target for cardiovascular diseases is limited by the lack of novel agonist scaffolds. Recently, active-like conformations for this receptor have been crystallized bound to agonists, showing conformational changes in key binding site residues compared to antagonist-bound A2AAR structures. In order to discover novel non-nucleoside A2AAR agonists, we carried out docking screens of 6.7 million commercially available molecules against active-like A2AAR structures, and found that nine out of the 20 predicted agonists were confirmed as potent A2AAR ligands in binding assays. However, none of these activated any of the AR subtypes. The difficulties to discover AR agonists using structure-based methods are hypothesized to originate from i) the limited atomic-level understanding of the activation mechanism and ii) a chemical bias towards AR antagonists in commercially available chemical libraries. In particular, calculation of 3D properties for the screened library revealed that its composition was found to strongly reduce the likelihood of discovering AR agonists, which is also a reflection of the higher molecular complexity required for AR activation. Extension of this analysis to other pharmaceutically relevant GPCRs such as adrenergic, serotonin, and purinergic receptors suggested that library screening may not be a suitable approach for targets requiring a complex receptor-ligand interaction network. The results of this study are expected to contribute to the development of novel A2AAR agonists and to the tailored use of structure-based approaches in drug discovery.

Molecular docking screens for the discovery of novel A2A adenosine receptor agonists: Are there any in chemical libraries?

249th National Meeting (2015)

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