Enabling Technologies to Facilitate Natural Product‐Based Drug Discovery from African Biodiversity

In the experience of the US National Cancer Institute, African biodiversity has been the source of several promising anticancer drugs. Analogues of the combretastatins are in advanced clinical trials, while conjugates of maytansine analogues with trastuzumab are showing great promise in the treatment of HER2-positive forms of breast cancer which have proved resistant to treatment with trastuzumab and lapatinib. Since 1987, the NCI, through contracts with Missouri Botanical Garden and Coral Reef Research Foundation, has undertaken plant and marine organism collections, respectively, in several African countries. In most instances, agreements based on the NCI Letter of Collection or Memorandum of Understanding were signed with the source-country authorities or qualified organizations, but in two cases where such agreements were not finalized, the necessary collection and export permits were obtained, and the NCI is totally committed to the terms of the LOC. The discovery of the anti-HIV-active compound michellamine B has emphasized the need for source countries to establish policies governing the exploration of their biological diversity for the discovery and development of novel bioactive molecules.

More than a billion people suffer from neglected tropical diseases (NTDs) which predominantly afflict people too poor to constitute a market attractive to private-sector research and development (R&D) investment. The discovery of antiparasitic new chemical entities (NCEs) based on ethnopharmacological approaches represents a major strategy for harnessing African biodiversity in the search for new drugs to combat NTDs as well as to address the ongoing emergence of resistance by causative protozoa. The ethnopharmacological use of medicinal plants for the treatment of parasitic diseases is well documented since ancient times, and the lessons learned from the application of such a strategy to the discovery of antiparasitic drugs are very well exemplified by the isolation of the first antimalarial drug quinine from Cinchona succirubra (Rubiaceae) and the currently widely prescribed antimalarial artemisinin from Artemisia annua. This chapter mainly highlights our experience in finding antiparasitic molecules with special bias towards the treatment of malaria, leishmania and trypanosomiasis. This chapter focuses on the disease burden of these neglected diseases, the challenges facing African scientists involved in this field of enquiry, and finishes up with some perspectives and conclusions. Due to the high number of natural products tested against the aforementioned protozoa in past years, the discussion is limited to some selected compounds from our own research. Research in our laboratory during the last 2 decades has mainly been directed towards the discovery of natural molecules active against NTDs. The compounds covered in this chapter highlight some selected examples of diverse secondary plant metabolites including sesquiterpenes, diterpenes, tripterpenes, tetranortriterpenes (limonoids) as well as acetogenins, flavonoids, lignans and alkaloids. This chapter also covers essential aspects related to the problems confronting African scientists who are currently engaged in this endeavour and suggests a strategy and mechanism streamlining drug discovery against NTDs.

BackgroundSouth African Natural Compounds Database (SANCDB; https://sancdb.rubi.ru.ac.za/) is the sole and a fully referenced database of natural chemical compounds of South African biodiversity. It is freely available, and since its inception in 2015, the database has become an important resource to several studies. Its content has been: used as training data for machine learning models; incorporated to larger databases; and utilized in drug discovery studies for hit identifications.DescriptionHere, we report the updated version of SANCDB. The new version includes 412 additional compounds that have been reported since 2015, giving a total of 1012 compounds in the database. Further, although natural products (NPs) are an important source of unique scaffolds, they have a major drawback due to their complex structure resulting in low synthetic feasibility in the laboratory. With this in mind, SANCDB is, now, updated to provide direct links to commercially available analogs from two major chemical databases namely Mcule and MolPort. To our knowledge, this feature is not available in other NP databases. Additionally, for easier access to information by users, the database and website interface were updated. The compounds are now downloadable in many different chemical formats.ConclusionsThe drug discovery process relies heavily on NPs due to their unique chemical organization. This has inspired the establishment of numerous NP chemical databases. With the emergence of newer chemoinformatic technologies, existing chemical databases require constant updates to facilitate information accessibility and integration by users. Besides increasing the NPs compound content, the updated SANCDB allows users to access the individual compounds (if available) or their analogs from commercial databases seamlessly.Graphic abstract