In the course of screening off-target interactions of ring-constrained nucleosides that were designed as potent ligands of the A3 adenosine receptor (AR), unanticipated μM affinity at other G protein-coupled receptors (GPCRs) was detected. The nucleoside analogues contained a fused bicyclo[3.1.0]hexane ring system in place of ribose, which is termed “methanocarba”, that enforced a North (N) envelope conformation. We therefore explored the structure-activity relationship (SAR) of functionalized (N)-methanocarba adenosine derivatives at the unconventional targets in an effort to optimize affinity while simultaneously reducing AR affinity. Depending on the substitution pattern around the rigidified nucleoside scaffold, we achieved nM affinity at 5HT2B serotonin receptors and other GPCRs. In order to understand the off-target interactions, we set up a molecular modeling pipeline, which consisted of Induced Fit docking calculations followed by GPU-accelerated molecular dynamics (MD) simulations and re-docking on selected MD-refined protein conformations. We suggested binding modes that supported the SAR at individual receptors on the basis of the structural ligand-protein complementarity and the temporal evolution of ligand-protein interactions in a membrane-embedded solvated environment. Our modeling approach will aid the design of additional structural analogues that either eliminate or enhance off-target activities and can serve as an example for the analysis of unrelated structural families at other targets.

Scaffold repurposing of ring-constrained nucleosides: A molecular modeling perspective

253rd National Meeting (2017)

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