Possibilities and Examples of Metabonomics in Drug Discovery and Development
In literature several possibilities of analyzing and interpreting metabonomic studies are reported. All these methods can be aplied in drug discovery and development and are briefly explained here. Examples for the second, third and fourth method are demonstrated on the following examples.
The first approach is monitoring the complete visible metabolome (entity of endogenous metabolites) without assigning each metabolite. This approach is based on the concept of drug likeness. This means that drugs with similar metabolic effects are supposed to have similar toxic effects. Thereby complete spectra of a study are matched to spectra of different studies usually stored in a database. Consequently toxicity is predicted on the basis of the most similar studies. The first approach with the largest database behind is the expert system "Magic 80" implemented during the COMET project (Consortium of Metabonomics). As long as metabolites are not identified, it is unclear why studies are similar.
In the second approach specific biomarkers are monitored. This means that only the signals of these biomarkers have to be monitored. Thereby no special method or assay has to be developed, as NMR spectra contain automatically all signals of all analytes, which are present at a certain concentration. An example of monitoring a specific biomarker for the detection of phospholipidosis is shown in the next section.
The third approach uses the fact that biomarkers, which are unspecific by themselves, can be specific when combined in a pattern. This means that a pattern of biomarkers has to be monitored for specifically determining certain effects. Examples concerning biomarkers for nephrotoxicity, hepatotoxicity and gut microflora effects are shown later.
As metabonomics is an unbiased method, also unknown biomarkers can be seen in contrast to typical clinical chemistry approaches. Thus the presence of new metabolites can be detected. Metabonomics also provides the possibility for determining the structure of these new metabolites. Some examples of a structure elucidations with the help of a chromatiographic separation and without a chromatographic separation are shown later.
Monitor changes of complete unassigned metabolome
Monitor changes of specific biomarkers
Monitor changes of specific patterns of unspecific biomarkers
Identify new unknown biomarkers
Possibilities of analyzing and interpreting metabonomic studies.