Natural products historically have been a rich source of lead molecules in drug discovery, based on their capability to create unique and diverse chemical structures. However, it is also true that the vast number of metabolites typically present in natural products and their huge dynamic range results in the loss of many possibly bioactive natural compounds, becoming an inextricable obstacle for drug development. Recently, new strategies which favour a holistic approach as opposed to the traditional reductionist methods used previously, have been introduced with the purpose of overcoming the bottlenecks in natural product research. This approach is based on the application of new technologies, including metabolomics, for example. Metabolomics allows a systematic study of a complex mixture such as a phytochemical preparation, which can be linked to observations obtained through biological testing systems without the need for isolating active principles. This may put drug discovery from natural products back in the limelight again. In this review paper, the description of some examples of successful metabolomics applications in several important fields related to drug discovery from natural sources aims at raising the potential of metabolomics in reducing the gap between natural products (NP) and modern drug discovery demand. Copyright © 2010 John Wiley & Sons, Ltd.

A large number of plant metabolites has provided as an incomparable chemical source for drug development. However, the wide range of the polarity of metabolites has been a big obstacle for full use of the chemical diversity. The initial step conventional extraction method by a single solvent does not make use of all the metabolites contained in plants. Also, it takes a long time to confirm the target activity of a single compound because of tedious separation steps. To solve the problem, a new extraction method coupled to NMR-based metabolomics is applied to identify bioactive natural products. A comprehensive extraction method consisting of a continuous flow of solvent mixtures through plant material was developed to provide extracts with a wider chemical variety than those yielded with a single solvent extraction. As the model experiment, (1)H NMR spectra of the extracts obtained from the comprehensive extraction of Orthosiphon stamineus were subjected to multivariate data analysis to find its adenosine A1 binding activity. On the basis of the results, two flavonoids from a large number of chemicals were clearly verified to show the adenosine A1 binding activity without any further purification steps. This method could provide a solution to the major drawbacks of natural products in drug development.

Orthosiphon stamineus Benth. ( Orthosiphon Grandiflorus Bold. or Clerodendranthus spicatus Thunb.) is an Indonesian medicinal herb traditionally used for diseases such as hypertension, diabetes, and kidney stones. Despite the importance of this last application, there are very few reports on it. Diuretic action is an important factor in kidney stone treatment, as an increase in the volume of fluid flowing through the kidney will help to dissolve the stones, assist their passing to avoid further retention, and flush out the deposits. Among the diverse roles of adenosine A (1) receptor antagonists in renal protection, many studies have shown that they can induce diuresis and sodium excretion. A bioassay-guided fractionation of a methanol-water extract of Orthosiphon stamineus leaves using the adenosine A (1) receptor binding assay resulted in the isolation of seven methoxy flavonoids as active ligands with K(i) values in the micromolar range. The Hill slope values are not significantly different from unity (within 0.9 - 1.4), which indicates the antagonist effect to A (1)-R. The results of this study thus provide a scientific foundation for the traditional use ofOrthosiphon stamineus in kidney stone treatment, as the affinity of the active compounds isolated from it as adenosine A (1) receptor ligands allows them to be associated with diuretic activity, which is one possible treatment for renal lithiasis.