Innovative strategies for the discovery of lead structures from nature

Natural products have been the most significant source of drugs and drug leads in history. One reason is certainly the ability of nature to produce a fantastic array of structurally complex and diverse molecules. Since less than 15% of the globe's biodiversity has been tested for biological activity, a large number of natural lead compounds is still unexplored [1]. The challenge is how to gain access to this diverse chemical space efficiently and effectively. Well established strategies for the discovery of new biologically active compounds are the ethnopharmacological, the chemotaxonomic and the random approach. In our laboratory we prioritize the first one. Based on ethno-pharmacological data we could recently identify a non toxic plant compound which seems to be a promising lead candidate for the prevention and treatment of intimal hyperplasia of venous bypass grafts.

An innovative strategy is the prediction of bioactive natural products (i.e. virtual hits) by means of i) pharmacophore-based virtual screening (VS) supported by docking experiments and ii) the parallel screening concept, which allows forecasting the correct pharmacological target for single molecules. Basic principles, requirements and limitations of VS strategies for discovering new lead structures from nature will be discussed. Their applicability in the natural product drug discovery process will be illustrated with some examples as part of an ongoing project focused on natural compounds acting as SMAC mimetics, thus targeting the BIR3 domain of XIAP. This protein is a member of the inhibitor of apoptosis protein (IAP) family which is antagonizing apoptosis by interaction with caspases.

All of these drug discovery approaches have strengths and also limitations. Therefore, an integrative concept combining different strategies, classical and innovative ones, and gathering as many information as possible from different fields, e.g. traditional medicine, botany, phytochemistry and pharmacology is required in order to guarantee a maximum of efficacy in natural product drug discovery.

References: 1. Cragg, GM. et al. (2005) Pure Appl Chem 77:7–24.