Survey of ribose ring pucker of signaling nucleosides and nucleotides

Abstract

The ribose of protein-bound nucleosides and nucleotides displays preferred conformations (usually either North or South), which can be exploited to design enhanced analogues having chemically fixed conformations. We introduce a computational protocol for assembling data from the protein database (PDB) on the ribose and ribose-like conformation of small molecule ligands when complexed with purinergic signaling proteins (including receptors, enzymes and transporters, and related intracellular pathways). Some targets prefer exclusively North (adenosine and P2Y 1 receptors, CD73, adenosine kinase ATP/ADP-binding site, adenosine deaminase), others prefer South (P2Y 12 receptor, E-NTPDase2) or East (adenosine kinase substrates), while others (P2XRs) allow various conformations.

Purinergic Signaling: Impact of GPCR Structures on Rational Drug Design

“…A focus on sterically constrained substitutes for the ribose ring identified the (N)‐methanocarba modification (present in 20 ‐ 23 ) as a general substitution that maintains an A 3 AR‐preferred conformation and is compatible with AR activation and suitable for combination with other A 3 AR‐enhancing modifications to further increase A 3 AR selectivity [71] . The preference for the ribose ring (N)‐conformation in the AR‐bound nucleosides has now been confirmed with the experimental structures of agonist‐ bound A 2A and A 1 ARs [74] . The ribose ring substitution with a (N)‐methanocarba ring system thus has the effect of constraining the agonists in a receptor‐preferred conformation.…”

Structure–Activity Relationship of 3-Methylcytidine-5′-α,β-methylenediphosphates as CD73 Inhibitors

“…By comparison, the (S)-methanocarba analogue of 28 in the simple uridine series was inactive at 1 μM, but optimized analogues were not prepared . The X-ray structures of bound nucleotides in CD73 display an N ribose conformation, consistent with the inhibition by 29 . , …”

“…Puckering analysis was accomplished with an in-house python script, with minor modification of what was reported previously. , …”

“…28 Furthermore, inspection of the reported CD73 X-ray structures indicates that an (N)-ribose conformation is present. 37 Therefore, (N)-methanocarba analogues 28 and 29 were prepared (Scheme 4) by adapting reported procedures. 38,39 Sugar protection by acetylation was performed using the standard method with acetic anhydride to afford intermediate 65.…”

“…28 The X-ray structures of bound nucleotides in CD73 display an N ribose conformation, consistent with the inhibition by 29. 27,37 An N-benzyl urea derivative 30 (71.5 nM) was only a moderately potent CD73 inhibitor compared to 9, indicating the advantage of the 4-oxoimino linkage. One 5′-diphosphate analogue, 5-fluorouracil derivative 31, was found to be a weak inhibitor with a K i of 2.54 μM.…”