Natural products are a diverse and

Natural products are a diverse and interesting source for the discovery of new lead structures (Newman and Cragg, 2016). After a successful era of natural product research, many pharmaceutical companies stopped their investment in natural product-driven drug discovery in the 1990s. The reason behind this step were the advantages of combinatorial synthesis and high-throughput screening (HTS) of chemical libraries over natural product libraries (Koehn and Carter, 2005; Li and Vederas, 2009; Shen, 2015). Major obstacles in HTS of natural product libraries arise from their heterogeneity and complexity. Hits obtained from extracts need to be purified normally guided by biological assays in order to identify the active constituents. Furthermore, the concentrations of the individual components of a mixture are not known. If an active ro bio 2 is only present in trace amounts, it might not be detected via HTS, whereas if it is present in very high amounts, it might interfere with or perturb the assay. Another major disadvantage of natural products is that their supply can be limited either because the availability of the source is limited or because the synthesis is not feasible. A further drawback of natural products is that the isolation and purification of the active compound can be very difficult, especially if the target compound constitutes less than 1% of the weight of the extract (Koehn and Carter, 2005). Notably, natural product research has gained new attention in recent years, as several technological advances helped to overcome many of the above mentioned disadvantages of natural product research (Koehn and Carter, 2005; Li and Vederas, 2009; Shen, 2015). For instance, the identification and structure elucidation of unknown compounds is facilitated by high-performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESI-MS) and by advances in high-resolution nuclear magnetic resonance (NMR) technologies (Koehn and Carter, 2005; Li and Vederas, 2009; Strege, 1999). In some HTS assays, the problem of light-scattering interferences or fluorescing compounds can be resolved by lifetime discriminated polarization or by simply raising the concentration of the fluorophore (Fowler et al., 2002; French et al., 1998; Koehn and Carter, 2005; Turek-Etienne et al., 2003). Developments in the field of metabolic engineering and microbial cultivation as well as advances in genetic methods help to solve the “supply problem” of natural products and hold promise for the development of natural product-derived drugs (Khosla and Keasling, 2003; Koehn and Carter, 2005; Ling et al., 2015; Shen, 2015). Natural products have chemically diverse structures that differ from synthetic and combinatorial compounds in several aspects. In general, they are sterically more complex than their synthetic counterparts, have a higher molecular weight and they incorporate more oxygen atoms than synthetics but less nitrogen, halogen and sulphur atoms. Moreover, natural products contain more fused, bridged or spiro ring systems than combinatorial compounds and they usually have a higher amount of solvated hydrogen-bond donors and acceptors in comparison to combinatorial compounds (Feher and Schmidt, 2003; Henkel et al., 1999; Koehn and Carter, 2005; Lahlou, 2013). Natural products do not only show structural and chemical diversity, but also biodiversity and profuse functionality (Jones et al., 2006; Koehn and Carter, 2005; Shen, 2015). They are often viewed as so-called privileged structures (Evans et al., 1988) as they are capable of interacting with multiple proteins or other biological targets (Koehn and Carter, 2005; Lahlou, 2013; Shen, 2015). They have been produced in living systems where they have been refined under evolutionary pressure and a large portion of natural products has advantageous pharmacokinetic properties (Feher and Schmidt, 2003; Firn and Jones, 2003; Jones et al., 2006; Koehn and Carter, 2005; Lam, 2007; Wink, 2003). Even if a natural product itself cannot be used as a therapeutic drug due to supply problems, for cost reasons or unfavorable bioavailabiliy, it may help to understand the interaction with a specific target or it may be used as a lead for synthetic mimetics (Koehn and Carter, 2005). Moreover, studying their pharmacological profile may deliver scientific knowledge for ethnopharmacologically used products.