Network pharmacology: the next paradigm in drug discovery

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    1698 Citations (Scopus)

    Abstract

    The dominant paradigm in drug discovery is the concept of designing maximally selective ligands to act on individual drug targets. However, many effective drugs act via modulation of multiple proteins rather than single targets. Advances in systems biology are revealing a phenotypic robustness and a network structure that strongly suggests that exquisitely selective compounds, compared with multitarget drugs, may exhibit lower than desired clinical efficacy. This new appreciation of the role of polypharmacology has significant implications for tackling the two major sources of attrition in drug development - efficacy and toxicity. Integrating network biology and polypharmacology holds the promise of expanding the current opportunity space for druggable targets. However, the rational design of polypharmacology faces considerable challenges in the need for new methods to validate target combinations and optimize multiple structure-activity relationships while maintaining drug-like properties. Advances in these areas are creating the foundation of the next paradigm in drug discovery: network pharmacology.

    Original languageEnglish
    Pages (from-to)682-690
    Number of pages9
    JournalNature Chemical Biology
    Volume4
    Issue number11
    DOIs
    Publication statusPublished - Nov 2008

    Keywords

    • SACCHAROMYCES-CEREVISIAE GENOME
    • PROTEIN-INTERACTION NETWORKS
    • DESIGNING MULTIPLE LIGANDS
    • ANTIBACTERIAL DISCOVERY
    • MULTICOMPONENT THERAPEUTICS
    • PHARMACEUTICAL-INDUSTRY
    • SELECTIVE OPTIMIZATION
    • TARGET RELATIONSHIPS
    • SYNTHETIC-LETHALITY
    • METABOLIC NETWORKS

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