Allo-network drugs: harnessing allostery in cellular networks

Abstract

Allosteric drugs are increasingly used because they produce fewer side effects. Allosteric signal propagation does not stop at the 'end' of a protein, but may be dynamically transmitted across the cell. Here, we propose that the concept of allosteric drugs can be broadened to allo-network drugs, whose effects can propagate either within a protein, or across several proteins, to enhance or inhibit specific interactions along a pathway. We posit that current allosteric drugs are a special case of allo-network drugs, and suggest that allo-network drugs can achieve specific, limited changes at the systems level, and in this way can achieve fewer side effects and lower toxicity. Finally, we propose steps and methods to identify allo-network drug targets and sites outlining a new paradigm in systems-based drug design.

14 pages, 4 figures, 69 references, a cover story of the 2011 December issue of Trends in Pharmacological Sciences

References in corpus (3)

• Induced fit, conformational selection and independent dynamic segments: an extended view of binding events
• The efficiency of multi-target drugs: the network approach might help drug design
• Uniformly curated signaling pathways reveal tissue-specific cross-talks and support drug target discovery

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• Targets of drugs are generally, and targets of drugs having side effects are specifically good spreaders of human interactome perturbations
• Perturbation centrality and Turbine: a novel centrality measure obtained using a versatile network dynamics tool
• Attractor structures of signaling networks: Consequences of different conformational barcode dynamics and their relations to network-based drug design
• Potential application of network descriptions for understanding conformational changes and protonation states of ABC transporters