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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    • "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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    ABSTRACT: For decades, the development of selective compounds has been the main goal for chemists and biologists involved in drug discovery. However, diverse lines of evidence indicate that polypharmacological agents, i.e. those that act simultaneously at various protein targets, might show better profiles than selective ligands, regarding both efficacy and side effects. On the other hand, the availability of the crystal structure of different receptors allows a detailed analysis of the main interactions between drugs and receptors in a specific binding site. Neuronal nicotinic acetylcholine receptors (nAChRs) constitute a large and diverse family of ligand-gated ion channels (LGICs) that, as a product of its modulation, regulate neurotransmitter release, which in turns produce a global neuromodulation of the central nervous system. nAChRs are pentameric protein complexes in such a way that expression of compatible subunits can lead to various receptor assemblies or subtypes. The agonist binding site, located at the extracellular region, exhibits different properties depending on the subunits that conform the receptor. In the last years, it has been recognized that nAChRs could also contain one or more allosteric sites which could bind non-classical nicotinic ligands including several therapeutically useful drugs. The presence of multiple binding sites in nAChRs offers an interesting possibility for the development of novel polypharmacological agents with a wide spectrum of actions. Copyright © 2015. Published by Elsevier Ltd.
    Pharmacological Research 08/2015; In Press(Online). DOI:10.1016/j.phrs.2015.08.018 · 4.41 Impact Factor
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    • "Until recently, potential antimicrobial compounds were screened against single pathogen targets in culture, followed by separate host-cell toxicity assessment. Toxicity testing is undoubtedly a key component in progressing drug discovery (Hopkins 2008). As the targets of the antifungal compounds are eukaryotic fungal cells, which share many characteristics (e.g. the fungal cell membrane component , ergosterol and mammalian cholesterol) with mammalian cells (Pierce and Lopez-Ribot 2013), selectivity of the antifungals is often difficult to predict. "
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    ABSTRACT: AimsThis study describes a novel in vitro assay that simultaneously determines antifungal efficiency and host cell toxicity using suspensions of human leukemic cells (HL-60) infected with Candida albicans.Methods and ResultsThe effect of Candida infection on host cell viability was evaluated by microscopy of trypan blue stained cells and lactate dehydrogenase (LDH) activity. The in vitro ‘drug potency assay’ utilized the Cell Counting Kit-8 and measured post antifungal treatment viability of Candida-infected HL-60 cells and ability of the antifungal to prevent infection. LDH activity showed that 42% ± 4.0 and 85.3% ± 7.40 of HL-60 cells were killed following Candida infection at multiplicity of infection (MOI) of 1:1 and 1:5, respectively. Using the assay, the antifungal nystatin (0.78-25 μmol l−1) was found to inhibit C. albicans infection as seen by significantly increased viability of HL-60 cells. Using the assay, cytotoxicity of nystatin towards infected HL-60 cells was evident at higher concentrations and this was also confirmed by propidium iodide staining.Conclusions An assay using undisturbed cell suspension conditions was successfully developed for assessing selectivity of antifungal therapy in the host-Candida environment.Significance and Impact of the StudyThe assay employing Candida infection of host cell suspensions represents a promising method for testing interactions of antifungal compounds with both fungal and host cells.This article is protected by copyright. All rights reserved.
    Journal of Applied Microbiology 04/2015; 119(1). DOI:10.1111/jam.12817 · 2.48 Impact Factor
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    • "It is increasingly clear that aging is regulated by complex networks of parallel pathways. This produces complex interactions, so that single compounds will not likely be effective at lifespan extension (Hopkins 2008). Rather, multi-target drugs and combinatorial therapies are likely to be more efficacious (de Magalhaes et al. 2012). "
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    ABSTRACT: Comparative biogerontology has much to contribute to the study of aging. A broad range of aging rates has evolved to meet environmental challenges, and understanding these adaptations can produce valuable insights into aging. The supra Phylum Lophotrochozoa is particularly understudied and has several groups that have intriguing patterns of aging. Members of the lophotrochozoan phylum Rotifera are particularly useful for aging studies because cohort life tables can be conducted with them easily, and biochemical and genomic tools are available for examining aging mechanisms. This paper reviews a variety of caloric restriction regimens, small molecule inhibitors, and dietary supplements that extend rotifer lifespan, as well as important interactions between caloric restriction and genotype, antioxidant supplements, and TOR and JNK pathways, and the use of RNAi to identify key genes involved in modulating the aging response. Examples of how rapamycin and JNK inhibitor exposure keeps mortality rates low during the reproductive phase of the life cycle are presented, and the ease of conducting life table experiments to screen natural products from red algae for life extending effects is illustrated. Finally, experimental evolution to produce longer-lived rotifer individuals is demonstrated, and future directions to determine the genetic basis of aging are discussed.
    Invertebrate Reproduction and Development 01/2015; 59(1):5-10. DOI:10.1080/07924259.2014.925516 · 0.61 Impact Factor
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