Metabolomic and Metabonomic  Technologies for Drug Discovery

Metabolomics is the study of small molecules and their interactions within an organism, which is critical to the drug-discovery process. The importance of metabolomic studies is indicated by the finding that a large proportion of the B6000 genes present in the genome of Saccharomyces cerevisiae and of those sequenced in other organisms, encode proteins of unknown function. Many of these genes are ‘silent’, i.e. they show no overt phenotype, in terms of growth rate or other fluxes, when they are deleted from the genome.

How the intracellular concentrations of metabolites can reveal phenotypes for proteins active in metabolic regulation has been demonstrated. Quantification of the change of several metabolite concentrations relative to the concentration change of one selected metabolite can reveal the site of action, in themetabolic network,  of a silent gene. In the same way , comprehensiveanalyses of metabolite concentrations in mutants, providing ‘metabolic snapshots’, can reveal functions when snapshots from strains deleted for unstudied genes are compared to those deleted for known genes.
An approach combining proteomics with metabolomics creates a new platform for identifying and validating metabolite biomarkers important to the development of safe and effective drugs. The unique combination of gene expression profiling (determining the level of activity of genes in an organism at a specific time), metabolic profiling (determining the identity and quantities of chemicals in an organism at a specific time) and phenotypic profiling (measuring the physical and chemical characteristics of an organism at a specific time), with data from all systems and analysed by bioinformatics, creates a new paradigm for industrialising functional genomics.
Metabonomics is a systems approach to investigate the metabolic consequences of drug exposure, disease processes and genetic modification whereas metabolomics is the measurement of metabolite concentrations in cell systems. It is important to direct the timing of
proteomic and genomic studies to maximise the probability of observing useful biological transitions that are indicative of function. Although anumber of  spectroscopic methods have been used, NMR spectroscopy is considered to be one of the most powerful methods for generating multivariate metabolic data. An NMR-based systems approach is used for drug toxicity screening to aid lead compound selection. Metabolic phenotyping (metabotyping) is also used for investigating the metabolic effects of genetic modification and modelling of human disease processes. One deliberate gene knockout can produce several metabolic disturbances. Metabonomics can thus be used as a functional genomics tool with applications in various stages of drug discovery and development.