Local and global modes of drug action in biochemical networks

It is becoming increasingly accepted that a shift is needed from the traditional target-based approach of drug development towards an integrated perspective of drug action in biochemical systems. To make this change possible, the interaction networks connecting drug targets to all components of biological systems must be identified and characterized.

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.