Adenosine receptors (AR) exert a general cytoprotective activity in the organism, promoting anti-inflammatory response and angiogenesis, protecting tissue from ischemic damage through precondition, and raising oxygen levels in hypoxia. hA3AR is less widely distributed than other AR subtypes and is a validated therapeutic target, with agonists potentially useful in autoimmune inflammatory and cardiovascular diseases, cancer and neuropathic pain. Structure-activity relationships of adenosine-based A3AR agonists highlight an enhanced affinity when the ribose ring is substituted by a [3.1.0]bicyclohexyl (methanocarba) moiety, conformationally constraining the ring in the North conformation ((N)-methanocarba isomer), and the aim of this work is to analyze the conformational requirements of A3AR-bound agonists. To probe ribose puckering in the bound state, we developed an automated procedure to analyze the ribose ring conformation of nucleosides bound to proteins deposited in the Protein Data Bank (PDB). No experimental A3AR structure is available, but the highly sequentially similar A1AR and A2AAR structures were determined, and the preferred nucleoside agonists puckering was observed to be the North. To investigate A3AR agonists, we built a homology model for the receptor and performed a molecular modeling study to compare a (N)-methanocarba agonist, MRS7334 (Ki, hA3AR, 0.28 nM), and its less potent ribose analogue MRS7432 (Ki, hA3AR, 2.30 nM). A hypothetical binding mode at the A3AR orthosteric binding site was predicted using molecular docking and remained stable during 30 ns molecular dynamics simulations, maintaining a typical pattern of interactions with the receptor. The conformational space explored by the A3AR-bound ribose ring of MRS7432 appeared reduced as compared to the free state, and this phenomenon was not observed for the constrained (N)-methanocarba MRS7334. This suggested that the lower affinity of ribose-containing agonists compared to (N)-methanocarba derivatives can be explained by a conformational entropy loss upon binding.

Ribose and ribose-like ring puckering in adenosine receptor-bound nucleosides

ACS Spring Meeting 2021

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