Caithness Biotechnologies: Natural product libraries for drug discovery Harnessing Nature for drug discovery
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No decrease in rate of discovery of new natural product scaffolds between 1990 and 2015


Natural product libraries for drug discovery


No decrease in rate of discovery of new natural product scaffolds between 1990 and 2015

It has been claimed that the rate of discovery of natural products with truly novel structures has been in decline since the ‘golden era’ of discovery between the 1950s and 1980s [1]. However, a new study published in PNAS reveals that the rate of discovery of novel scaffolds from natural sources has remained roughly at the same level since the peak was reached ~30 years ago [2].

Roger Linington at Simon Fraser University, Canada, and his co-workers applied rigorous definitions of compound similarity and used computational chemoinformatics to formally address this question [1]. By combining structures from published databases and searches of the more recent published literature, the team assembled a database of 52,395 unique marine and micro-organism-derived compounds discovered between 1941 and 2015. The researchers then calculated Tanimoto similarity scores between all molecule pairs in their database. The rate of discovery of those with a Tanimoto similarity score below 0.4 - i.e. a new scaffold - peaked at around 200 per year in the late 1980s. However, the rate of new scaffold discovery has remained at pretty much the same level until at least 2015.

The authors comment that this unabated rate of discovery is surprising, given the decline of interest in natural products from industry in the early 1990s. However, greater interest among workers in academia, together with improvements in compound identification and the mining of novel taxa from ever more remote niches, has maintained the healthy rate of new scaffold discovery.

The researchers also point out that when accounting for dereplication, ~1,500 novel natural product structures were also reported per year during the past 30 years. This indicates that although the majority of reported structures are variants of existing scaffolds, ~13% are compounds with no structurally related equivalent. Thus, even after 70 years of exploration, new scaffolds continue to be discovered.

Crucially, the authors point out that while much progress has been made in understanding of the structural diversity of natural products in recent years, very little information is available with respect to the potential bioactivities of these molecules. Indeed, of the tens of thousands of mammalian targets with potential for drug development, only a small fraction has been screened in any campaign, and only ~400 have been drugged successfully to date.

Together, these findings support the view that the recent slow-down in approval of natural product derived drugs is not due to a reduced rate of scaffold discovery. Instead, it is more likely a symptom of the refocusing of large pharmaceutical firms to synthetic library screening. A re-inclusion of the wealth inherent in Nature’s chemical space in modern screening programmes clearly retains great potential for the discovery of new compounds with therapeutic potential.

[1] Kong DX, Guo MY, Xiao ZH, Chen LL, Zhang HY. Historical variation of structural novelty in a natural product library. Chem Biodivers 8:1968-77 (2011)

[2] Pye CR, Bertin MJ, Lokey RS, Gerwick WH, Linington RG. Retrospective analysis of natural products provides insights for future discovery trends. Proc Natl Acad Sci USA 114:5601-5606 (2017)


Natural product libraries for drug discovery

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