A prospective, large library virtual screen against an activated �2-adrenergic receptor structure returned potent agonists, essentially to the exclusion of antagonists. In addition, two hits recapitulated the arrestin signaling bias of the co-crystal ligand. This functional fidelity has important implications in drug-design, as the ability to predict ligands with predefined signaling properties is highly desirable. Furthermore, we use virtual screening to predict ligands of pre-defined selectivity. We are searching for ligands with high affinity for dopamine and serotonin receptors, which mediate the therapeutic effects of anti-psychotic medications, and poor affinity for histamine receptor, which mediates serious metabolic side effects. This has led to selective molecules, but also to molecules with high affinity for the �anti-target� histamine receptor, raising important questions about false negatives in docking. Finally, using docking against structures of the M2 and M3 muscarinic receptor subtypes, we have identified novel binding chemotypes, some which show a functional selectivity.

G-protein coupled receptors in virtual screening: Functional fidelity and selectivity

245th National Meeting (2013)

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