Selective structure-based virtual screening for full and partial agonists of the ß2 adrenergic receptor

The recently solved high-resolution X-ray structure of the ß2 adrenergic receptor has been challenged for its ability to discriminate inverse agonists/antagonists from partial/full agonists. Whereas the X-ray structure of the ground state receptor was unsuitable to distinguish true ligands with different functional effects, modifying this structure to reflect early conformational events in receptor activation led to a receptor model able to selectively retrieve full and partial agonists by structure-based virtual screening. The use of a topological scoring function based on molecular interaction fingerprints was shown to be mandatory to properly rank docking poses and achieve acceptable enrichments for partial and full agonists only.

Chris de Graaf, Didier Rognan
August 28, 2008
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