Unraveling structural mechanisms of allosteric drug action

Ruth Nussinov*, Chung Jung Tsai

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

109 Scopus citations

Abstract

Orthosteric drugs block the active site to obstruct function; allosteric drugs modify the population of the active state, to modulate function. Available data lead us to propose that allosteric drugs can constitute anchors and drivers. The anchor docks into an allosteric pocket. The conformation with which it interacts is unchanged during the transition between the inactive and active states. The anchor provides the foundation that allows the driver to exert a 'pull' and/or 'push' action that shifts the receptor population from the inactive to the active state. The presence or absence of driver atom in an allosteric drug can exert opposite agonism. We map a strategy for driver identification and expect the allosteric trigger concept to transform agonist/antagonist drug discovery.

Original languageEnglish
Pages (from-to)256-264
Number of pages9
JournalTrends in Pharmacological Sciences
Volume35
Issue number5
DOIs
StatePublished - May 2014

Funding

FundersFunder number
National Institutes of HealthHHSN261200800001E
National Cancer InstituteZIABC010441

    Keywords

    • agonist
    • allosteric drug discovery
    • allostery
    • anchor atom
    • antagonist
    • driver atom
    • protocol

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