Network Pharmacology: The Next Paradigm in Drug Discovery

Division of Biological Chemistry and Drug Discovery, College of Life Science, University of Dundee, Dundee, UK.
Nature Chemical Biology (Impact Factor: 13). 11/2008; 4(11):682-90. DOI: 10.1038/nchembio.118
Source: PubMed


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.

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    • "All rights reserved. " polypharmacology " concept, now becoming of considerable importance in the discovery of new drugs [24]. "
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    • "Even though it is known that many currently used drugs act via interaction with multiple receptors [9] [11], the realization that these properties can be proactively pursued has generated a new trend in drug discovery, called polypharmacology, in which a desired therapeutic effect can be achieved by compounds acting on a selected range of pharmacological targets [12] [13] [14]. However, the rational design of multitarget drugs faces considerable challenges in the understanding and optimization of multiple structure-activity relationships [3] [4] [14] [15]. In fact, it is unclear to what extent rational design of polypharmacological drugs can be achieved for proteins functionally and/or structurally divergent [1] [8] [15]. "
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