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BMC Chemical Biology 2009
Local and global modes of drug action in biochemical networksAbstract: We here present an integrative analysis of the interactions between drugs and metabolism by introducing the concept of metabolic drug scope. The metabolic drug scope represents the full set of metabolic compounds and reactions that are potentially affected by a drug. We constructed and analyzed the scopes of all US approved drugs having metabolic targets. Our analysis shows that the distribution of metabolic drug scopes is highly uneven, and that drugs can be classified into several categories based on their scopes. Some of them have small scopes corresponding to localized action, while others have large scopes corresponding to potential large-scale systemic action. These groups are well conserved throughout different topologies of the underlying metabolic network. They can furthermore be associated to specific drug therapeutic properties.These findings demonstrate the relevance of metabolic drug scopes to the characterization of drug-metabolism interactions and to understanding the mechanisms of drug action in a system-wide context.There is a growing perception that the traditional approach for drug development has not been as effective as could be expected [1]. Although investments by pharmaceutical companies have been growing continuously in the last decades, the number of newly approved drugs has not followed the same trend [2,3]. Currently the main trend in drug design and development follows the target-based approach. The drug target is generally a single gene or gene product which has been clearly identified as having an action on the disease. Disease treatment seeks to modulate this action without affecting other processes in the organism. However, many diseases are multifactorial, and the current approach fails to take such systemic aspects into account [4-6]. The complex interactions between numerous molecular processes and pathways involved in diseases imply that any treatment targeting a local element will create secondary effects on the entire system. T
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