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

Abstract

ABSTRACT:The β 2 -adrenergic receptor (β 2 AR) is a G protein-coupled receptor (GPCR) and a well-explored target. Here, we report the discovery of 13 ligands, ten of which are novel, of this particular GPCR. They have been identified by similarity-and substructure-based searches using multiple ligands, which were described in an earlier study, as starting points. Of note, two of the molecules used as queries here distinguish themselves from other β 2 AR antagonists by their unique scaffold. The molecules described in this work allow us to explore the ligand space around the previously reported molecules in greater detail, leading to insights into their structure−activity relationship. We also report experimental binding and selectivity data and putative binding modes for the novel molecules.

Interrogating dense ligand chemical space with a forward-synthetic library

“…In terms of affinity, the present results might be considered lagging behind earlier virtual screens that we conducted (7,8). However, besides the top compounds (1 in ref.…”

“…7 and 3 in ref. 8), which can be considered outliers even in the context of their own campaigns, the remainder of the compounds identified here are in similar ranges. It can also not be ruled out that the protein fusions used in our assay lead to systematic affinity differences, therefore underestimating the affinity against the wild-type receptor.…”

“…We started the campaign from SCUBIDOO's "small" (S) subset of ∼10,000 products, to determine whether these would be enough to actually capture diverse molecules in the end. To select compounds for synthesis, we used docking, which we have shown earlier to be able to identify novel scaffolds for GPCR targets (7)(8)(9). To demonstrate that ligand selection can be tailored, we wished to explore the binding cavity of the β2AR in more detail.…”

Comparative Docking to Distinct G Protein–Coupled Receptor Conformations Exclusively Yields Ligands with Agonist Efficacy

“…A complementary docking calculation to the b 2 AR inactive can be helpful here but also includes the risk of incorrect predictions, because statistically, a favorable rank in the b 2 AR inactive , but not in the b 2 AR active , would be taken to indicate an antagonist or inverse agonist. That the discovery of this agonist from a b 2 AR inactive structure is an exception is supported by the fact that none of the ligands discovered in our earlier studies of docking to a b 2 AR inactive were agonists (Kolb et al, 2009;Schmidt et al, 2017).…”

“…The majority of discovered agonists, seven, originated from the dual reranking (7/22 molecules; 32%). The overall hit rate of 37% is at the upper end compared with other docking studies using the b 2 AR (Sabio et al, 2008;Kolb et al, 2009;Weiss et al, 2013;Schmidt et al, 2017;Chevillard et al, 2019) or related aminergic GPCRs (Carlsson et al, 2011;Kruse et al, 2013).…”