Selective structure-based virtual screening for full and partial agonists of the beta2 adrenergic receptor.
The recently solved high-resolution X-ray structure of the beta2 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.
de Graaf
Chris
C
Bioinformatics of the Drug, Institut Gilbert Laustriat, CNRS UMR 7175-LC1, Université Louis Pasteur Strasbourg, 74 Route du Rhin, 67401 Illkirch, France.
Rognan
Didier
D
D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D003198:Computer Simulation; D018360:Crystallography, X-Ray / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D007545:Isoproterenol / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D011412:Propanolamines / Q000737:chemistry; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D008024:Ligands; D011412:Propanolamines; C014382:carazolol; D007545:Isoproterenol