Natural Products in Drug Discovery

Corresponding Author:

Brownie Lee Department of Pharmacognosy, University of Vienna, Vienna, Australia E-mail: brownie_lee@uv.au

Abstract

Commentary

Natural products (NPs) have long been important in medication development, particularly for cancer and infectious disorders, but also for other therapeutic areas such as cardiovascular disease (statins) and multiple sclerosis (for example, fingolimod). In comparison to traditional synthetic compounds, NPs have unique properties that provide both benefits and problems to the drug discovery process. The scaffold variety and structural complexity of NPs are immense. When compared to synthetic compound libraries, they typically have a higher molecular mass, more sp3 carbon and oxygen atoms but fewer nitrogen and halogen atoms, more H-bond acceptors and donors, lower calculated octanol–water partition coefficients (cLogP values, indicating higher hydrophilicity), and greater molecular rigidity. Although the complexity of NP structures might be beneficial, creating structural analogues to investigate structure–activity connections and optimise NP leads can be difficult, especially if synthetic approaches are problematic. Furthermore, phenotypic assays are frequently used to identify NPbased therapeutic leads, and deconvolution of their molecular mechanisms of action can be time-consuming. Fortunately, both the creation of screening tests (for example, leveraging the potential of induced pluripotent stem cells and gene editing technologies) and efforts to discover the modes of action of active drugs have made significant progress.

Although the complexity of NP structures might be beneficial, creating structural analogues to investigate structure–activity connections and optimise NP leads can be difficult, especially if synthetic approaches are problematic. Furthermore, phenotypic assays are frequently used to identify NP-based therapeutic leads, and deconvolution of their molecular mechanisms of action can be time-consuming. Fortunately, both the creation of screening tests (for example, leveraging the potential of induced pluripotent stem cells and gene editing technologies) and efforts to discover the modes of action of active drugs have made significant progress. NP extracts are analysed for metabolite profiling using NMR spectroscopy or high-resolution mass spectrometry (HRMS), or combined approaches incorporating upstream liquid chromatography (LC), such as LC– HRMS, which may separate multiple isomers found in NP extracts. Furthermore, such integrated methods might combine HRMS and NMR, allowing the advantages of both techniques to be used simultaneously. NMR analysis of NP extracts is straightforward and repeatable, and it offers direct quantitative information as well as precise structural information. However, because of its poor sensitivity, it can only profile key ingredients.

Analytical breakthroughs that allow single-cell profiling of responses to bioactive compounds can help speed up NP-based drug development. By combining phospho-specific flow cytometry, single-cell chemical biology, and cellular barcoding with metabolomic arrays, Irish, Bachmann, Earl, and colleagues established a high-throughput method for metabolomic monitoring of bioactivity (characterized chromatographic microtitre arrays originating from biological extracts). The authors used this platform to look at single-cell responses in bone marrow biopsy samples from patients with acute myeloid leukaemia after they were exposed to microbial metabolomic arrays made from biosynthetically prolific bacteria extracts, which led to the discovery of new bioactive polyketides. NPs remain a promising source of scaffolds with a wide range of structural diversity and bioactivities that can be developed directly or used as a starting point for the development of new drugs. While high attrition rates in drug development continue to be a problem, NPs face additional challenges due to issues like accessibility, long-term supply, and IP restrictions. We think, however, that the scientific and technological advancements mentioned in this Review provide a solid foundation for NP-based drug development to continue making significant contributions to human health and lifespan.

Acknowledgement

None

Conflict of Interest

The author declares there is no conflict of interest.