Are Two Riboses Better Than One? The Case of the Recognition and Activation of Adenosine Receptors

Abstract

Traditionally, molecular recognition between the orthosteric site of adenosine receptors and their endogenous ligand occurs with a 1 : 1 stoichiometry. Inspired by previous mechanistic insights derived from supervised molecular dynamics (SuMD) simulations, which suggested an alternative 2 : 1 binding stoichiometry, we synthesized BRA1, a bis-ribosyl adenosine derivative, tested its ability to bind to and activate members of the adenosine receptor family, and rationalized its activity through molecular modeling.

2-Substituted (N)-Methanocarba A3 Adenosine Receptor Agonists: In Silico, In Vitro, and In Vivo Characterization

“…The top-scoring solutions illustrated a congruent orientation of the adenosine scaffold within the pocket, with the adenine ring forming a divalent H-bond with the side chain of N250, donating through its exocyclic N 6 –H group and accepting through its endocyclic N 7 nitrogen, and a face-to-face π–π stacking with the side chain of F168. Both interactions are highly conserved across the different AR subtypes and are required for the binding of both agonists and antagonists to the orthosteric binding site . Furthermore, the conformationally restrained (N)-methanocarba pseudoribose ring occupies the hydrophilic lower portion of the pocket, donating two H-bonds through its 2′ and 3′ hydroxyl groups to the side chains of H272 and S271, respectively, and a third between the 5′- N -methylcarboxamide moiety and the side chain of T94.…”

“…Chemical Synthesis. Novel (N)-methanocarba 5′-methylamide (3b−3d, 9−34) and 4′-truncated (37,38) derivatives (Table 1) were synthesized with the aim of identifying new A 3 AR full and/or partial agonists. [15][16][17][18][19]29 The presence of a 5′methylamide was shown previously to maximize agonism, while truncated analogues tend to have greatly reduced maximal efficacy (E max ).…”

“…Both interactions are highly conserved across the different AR subtypes and are required for the binding of both agonists and antagonists to the orthosteric binding site. 37 Furthermore, the conformationally restrained (N)-methanocarba pseudoribose ring occupies the hydrophilic lower portion of the pocket, donating two H-bonds through its 2′ and 3′ hydroxyl groups to the side chains of H272 and S271, respectively, and a third between the 5′-N-methylcarboxamide moiety and the side chain of T94.…”