Small-Molecule Positive Allosteric Modulators of the β2 -Adrenoceptor Isolated from DNA-Encoded Libraries

Molecular Pharmacology
Seungkirl AhnRobert J Lefkowitz

Abstract

Conventional drug discovery efforts at the β2-adrenoceptor (β2AR) have led to the development of ligands that bind almost exclusively to the receptor's hormone-binding orthosteric site. However, targeting the largely unexplored and evolutionarily unique allosteric sites has potential for developing more specific drugs with fewer side effects than orthosteric ligands. Using our recently developed approach for screening G protein-coupled receptors (GPCRs) with DNA-encoded small-molecule libraries, we have discovered and characterized the first β2AR small-molecule positive allosteric modulators (PAMs)-compound (Cmpd)-6 [(R)-N-(4-amino-1-(4-(tert-butyl)phenyl)-4-oxobutan-2-yl)-5-(N-isopropyl-N-methylsulfamoyl)-2-((4-methoxyphenyl)thio)benzamide] and its analogs. We used purified human β2ARs, occupied by a high-affinity agonist, for the affinity-based screening of over 500 million distinct library compounds, which yielded Cmpd-6. It exhibits a low micro-molar affinity for the agonist-occupied β2AR and displays positive cooperativity with orthosteric agonists, thereby enhancing their binding to the receptor and ability to stabilize its active state. Cmpd-6 is cooperative with G protein and β-arrestin1 (a.k.a. arrestin2) to stabilize ...Continue Reading

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Citations

Aug 17, 2018·Molecular Pharmacology·Xushan WangRobert F Bruns
Jul 30, 2020·The Journal of Biological Chemistry·Andrew G ReidenbachEric Vallabh Minikel
May 22, 2019·Expert Opinion on Drug Discovery·Guixian ZhaoXiaoyu Li
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Oct 30, 2020·Frontiers in Pharmacology·Dianne M Perez
Jan 9, 2021·Signal Transduction and Targeted Therapy·Dehua YangMing-Wei Wang
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Aug 25, 2021·Accounts of Chemical Research·Yinan Song, Xiaoyu Li
Aug 24, 2021·ACS Pharmacology & Translational Science·Adrián Gironda-MartínezDario Neri

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Methods Mentioned

BETA
X-ray
PCR
transfections
Transfection
glycosylation
size exclusion chromatography
amplicon sequencing
protein assay
Assay
Enzyme-Linked Immunosorbent Assay

Software Mentioned

GraphPad Prism
MicroCal Origin

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