Structure-based discovery of β ₂ -adrenergic receptor ligands

Abstract

Aminergic G protein-coupled receptors (GPCRs) have been a major focus of pharmaceutical research for many years. Due partly to the lack of reliable receptor structures, drug discovery efforts have been largely ligand-based. The recently determined X-ray structure of the ␤2-adrenergic receptor offers an opportunity to investigate the advantages and limitations inherent in a structure-based approach to ligand discovery against this and related GPCR targets. Approximately 1 million commercially available, ''lead-like'' molecules were docked against the ␤2-adrenergic receptor structure. On testing of 25 high-ranking molecules, 6 were active with binding affinities <4 M, with the best molecule binding with a Ki of 9 nM (95% confidence interval 7-10 nM). Five of these molecules were inverse agonists. The high hit rate, the high affinity of the most potent molecule, the discovery of unprecedented chemotypes among the new inhibitors, and the apparent bias toward inverse agonists among the docking hits, have implications for structure-based approaches against GPCRs that recognize small organic molecules.docking ͉ GPCR ͉ inverse agonists ͉ library bias ͉ ligand design

Small molecule inhibitors of Smoothened ciliary localization and ciliogenesis

“…To investigate whether the SA compounds resemble compounds with described biological activities, we used the similarity ensemble approach to screen the SA compounds against the ∼3,000 targets and 500,000 ligands of the ChEMBL database (42)(43)(44). This approach predicted that SA6 would be an Smo inhibitor, reflecting its similarity to the 1-amino-4-benzylphthalazine family of Smo inhibitors (45).…”

The structure of active opsin as a basis for identification of GPCR agonists by dynamic homology modelling and virtual screening assays

“…An early discrimination of the investigated ligands into these categories in silico is of high importance for pharmaceutical research. Most GPCR crystal structures represent an inactive state which has been considered to be capable for the discovery of antagonists and inverse agonists only [12][13][14]. To date, only the structure of opsin [15] and most recently structural models of active conformations of the b 2 -adrenergic receptor (B2AR) [16][17][18], the agonist-bound b 1 -adrenergic receptor [19] and a constitutively active rhodopsin [20] could be potentially used as a template for the modelling of active GPCRs and subsequent virtual screening for agonists.…”

Similarity- and Substructure-Based Development of β2-Adrenergic Receptor Ligands Based on Unusual Scaffolds

“…It was also the first pharmacologically relevant GPCR to succumb to crystallization in 2007. 3,4 In a previous work, 5 we have identified six ligands (originally labeled 1−6, and referred to as Q1−Q6 in this work to avoid confusion, Chart S1) of the β 2 AR through in silico docking studies, with affinities ranging from 9 nM to 3.2 μM. Notably, these included two molecules (5 and 6 in ref 5, denoted as Q5 and Q6, respectively, in the following) that did not follow the classical adrenaline-based scaffold.…”