5/15/2023 0 Comments Thomas raskin drugs![]() Following the identification of a crude extract with promising pharmacological activity, the next step is its (often multiple) consecutive bioactivity-guided fractionation until the pure bioactive compounds are isolated. To maximize the diversity of the extracted NPs, the biological material can be subjected to extraction with several solvents of different polarity. The choice of extraction method determines which compound classes will be present in the extract (for example, the use of more polar solvents will result in a higher abundance of polar compounds in the crude extract). The process begins with extraction of NPs from organisms such as bacteria. Steps in the process are shown in purple boxes, with associated key limitations shown in red boxes and advances that are helping to address these limitations in modern natural product (NP)-based drug discovery shown in green boxes. ![]() 17), as well as recent developments concerning benefit sharing linked to use of marine genetic resources 18. An additional layer of complexity relates to the regulations defining the need for benefit sharing with countries of origin of the biological material, framed in the United Nations 1992 Convention on Biological Diversity and the Nagoya Protocol, which entered into force in 2014 (ref. Furthermore, gaining intellectual property (IP) rights for (unmodified) NPs exhibiting relevant bioactivities can be a hurdle, since naturally occurring compounds in their original form may not always be patented (legal frameworks vary between countries and are evolving) 16, although simple derivatives can be patent-protected (Box 1). ![]() Accessing sufficient biological material to isolate and characterize a bioactive NP may also be challenging 15. ![]() Identifying the bioactive compounds of interest can be challenging, and dereplication tools have to be applied to avoid rediscovery of known compounds. 1), which may not be compatible with traditional target-based assays 14. NP screens typically involve a library of extracts from natural sources (Fig. Overall, the NP pool is enriched with ‘bioactive’ compounds covering a wider area of chemical space compared with typical synthetic small-molecule libraries 13.ĭespite these advantages and multiple successful drug discovery examples, several drawbacks of NPs have led pharmaceutical companies to reduce NP-based drug discovery programmes. Furthermore, their use in traditional medicine may provide insights regarding efficacy and safety. NPs are structurally ‘optimized’ by evolution to serve particular biological functions 1, including the regulation of endogenous defence mechanisms and the interaction (often competition) with other organisms, which explains their high relevance for infectious diseases and cancer. The increasing significance of drugs not conforming to this rule is illustrated by the increase in molecular mass of approved oral drugs over the past 20 years 12. Indeed, NPs are a major source of oral drugs ‘beyond Lipinski’s rule of five’ 11. These differences can be advantageous for example, the higher rigidity of NPs can be valuable in drug discovery tackling protein–protein interactions 10. They typically have a higher molecular mass, a larger number of sp 3 carbon atoms and oxygen atoms but fewer nitrogen and halogen atoms, higher numbers of H-bond acceptors and donors, lower calculated octanol–water partition coefficients (cLogP values, indicating higher hydrophilicity) and greater molecular rigidity compared with synthetic compound libraries 1, 6, 7, 8, 9. NPs are characterized by enormous scaffold diversity and structural complexity. NPs offer special features in comparison with conventional synthetic molecules, which confer both advantages and challenges for the drug discovery process. Historically, natural products (NPs) have played a key role in drug discovery, especially for cancer and infectious diseases 1, 2, but also in other therapeutic areas, including cardiovascular diseases (for example, statins) and multiple sclerosis (for example, fingolimod) 3, 4, 5.
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