Metabolomics and systems pharmacology: why and how to model the human metabolic network for drug discovery()

Metabolism represents the ‘sharp end’ of systems biology, because changes in metabolite concentrations are necessarily amplified relative to changes in the transcriptome, proteome and enzyme activities, which can be modulated by drugs. To understand such behaviour, we therefore need (and increasingly have) reliable consensus (community) models of the human metabolic network that include the important transporters. Small molecule ‘drug’ transporters are in fact metabolite transporters, because drugs bear structural similarities to metabolites known from the network reconstructions and from measurements of the metabolome. Recon2 represents the present state-of-the-art human metabolic network reconstruction; it can predict inter alia: (i) the effects of inborn errors of metabolism; (ii) which metabolites are exometabolites, and (iii) how metabolism varies between tissues and cellular compartments. However, even these qualitative network models are not yet complete. As our understanding improves so do we recognise more clearly the need for a systems (poly)pharmacology.