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The network as the target

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Abstract The conventional target centric model of drug discovery is pinned under the weight of prior success and the traditional problems of safety and efficacy for new molecules. An alternative to target centric drug development is to shift focus to the pathways that mediate both biology and pathophysiology. This method has the advantage of not requiring a priori knowledge of the small molecule target, but also comes with it several challenges including target determination. We suggest extending this notion more broadly across the drug discovery process using quantitative network structure‐activity relationships (QNSAR), and discuss the steps necessary to test the hypothesis that systems biology approaches can be used to improve the drug discovery process. Copyright © 2009 John Wiley & Sons, Inc. This article is categorized under: Translational, Genomic, and Systems Medicine > Therapeutic Methods

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Approval of new drugs by the FDA has stagnated over the last decade. The number of new molecular entities (NMEs) approved by the FDA is plotted for every year between 1996 and 2008. Blue bars represent the total number of NMEs, whereas red bars represent “priority” NMEs, that is, new drugs that are potentially a substantial advance over conventional therapies. Source: http://www.fda.gov/cder/index.html.

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Schematic comparison of QSAR and QNSAR. QSAR is a well‐developed tool of medicinal chemistry that establishes a rational framework for predicting and optimizing the properties of potential pharmaceuticals. Different compounds derived from a common scaffold (top panel) are used to perturb the function of a single protein target (left panel). A variety of different chemical, biophysical or functional assays may then be used to measure relevant properties of each compound. By assuming that similar compounds have similar properties, a variety of algorithms may be used to identify the structural features of small molecules most likely to correlate with useful chemical properties (bottom panel). We propose combining this approach with systems‐level biological data sets to aid drug discovery (right panel). Rather than focusing on a single protein target, systems approaches (e.g., transcriptional profiling and proteomics) can be used to determine how small molecules perturb entire signaling networks.

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