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Structure–Activity Relationship of Truncated 4′-Selenonucleosides: A3 Adenosine Receptor Activity and Binding Selectivity

Year: 2024

Type: article

Abstract: This study explored the impact of structural modifications on truncated 4′-selenonucleosides as ligands for the A 3 adenosine receptor (AR). We synthesized and evaluated a series of these compounds for their binding affinities, functional activities, and structural interactions by using computational modeling. The SAR study revealed that all compounds exhibited selective and notable hA 3 AR binding, among which 6l ( K i = 5.2 nM) and 6m ( K i = 5.7 nM) were found as the best binding compounds. The representative N 6 -cyclopropyl compound 6m was found to be a partial agonist, contrasting with the antagonist profiles of truncated 4′-oxo and 4′-thionucleosides. Computational docking highlighted 6m ’s unique interaction with Thr94 at the A 3 AR binding site. This research not only advances our understanding of A 3 AR ligand interactions but also highlights the potential of truncated 4′-selenonucleosides as effective A 3 AR modulators.

Source: ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.4c00344