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Polypharmacology of conformationally locked methanocarba nucleosides.

ABSTRACT: 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.

SUBMITTER: Jacobson KA

PROVIDER: S-EPMC5705437 | biostudies-other | 2017 Dec

REPOSITORIES: biostudies-other

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Polypharmacology of conformationally locked methanocarba nucleosides.

Jacobson Kenneth A KA Tosh Dilip K DK Toti Kiran S KS Ciancetta Antonella A

Drug discovery today 20170803 12

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 requ ...[more]

PMID: 28781163

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