Drug Discovery Today
Drug Discovery Today
5 years ago

Polypharmacology of conformationally locked methanocarba nucleosides

Polypharmacology of conformationally locked methanocarba nucleosides
A single molecular scaffold can be adapted to interact with diverse targets, either separately or simultaneously. Nucleosides and nucleotides in which ribose is substituted with bicyclo[3.1.0]hexane are an example of a versatile drug-like scaffold for increasing selectivity at their classical targets: kinases, polymerases, adenosine and P2 receptors. Also, by applying structure-based functional group manipulations, rigidified adenosine derivatives can be repurposed to satisfy pharmacophoric requirements of various GPCRs, ion channels, enzymes and transporters, initially detected as off-target activities. Recent examples include 5HT2B serotonin receptor antagonists and novel dopamine transporter allosteric modulators. This directable target diversity establishes rigid nucleosides as privileged scaffolds.

Graphical abstract

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The scope of action of nucleosides, widely used anticancer and antiviral drugs, is now extended to unconventional targets, including diverse receptors, enzymes and transporters, using a conformational lock.

Publisher URL: www.sciencedirect.com/science

DOI: S135964461730168X

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