Abstract
The screening and testing of extracts against a variety of pharmacological targets in order to benefit from the immense natural chemical diversity is a concern in many laboratories worldwide. And several successes have been recorded in finding new actives in natural products, some of which have become new drugs or new sources of inspiration for drugs. But in view of the vast amount of research on the subject, it is surprising that not more drug candidates were found. In our view, it is fundamental to reflect upon the approaches of such drug discovery programs and the technical processes that are used, along with their inherent difficulties and biases. Based on an extensive survey of recent publications, we discuss the origin and the variety of natural chemical diversity as well as the strategies to having the potential to embrace this diversity. It seemed to us that some of the difficulties of the area could be related with the technical approaches that are used, so the present review begins with synthetizing some of the more used discovery strategies, exemplifying some key points, in order to address some of their limitations. It appears that one of the challenges of natural product-based drug discovery programs should be an easier access to renewable sources of plant-derived products. Maximizing the use of the data together with the exploration of chemical diversity while working on reasonable supply of natural product-based entities could be a way to answer this challenge. We suggested alternative ways to access and explore part of this chemical diversity with in vitro cultures. We also reinforced how important it was organizing and making available this worldwide knowledge in an “inventory” of natural products and their sources. And finally, we focused on strategies based on synthetic biology and syntheses that allow reaching industrial scale supply. Approaches based on the opportunities lying in untapped natural plant chemical diversity are also considered.
Highlights
ON NATURAL COMPOUNDS IN DRUG DISCOVERYDrugs and Natural ProductsSeveral reviews, like the updated survey from Newman and Cragg (2016), pointed to the fact that many drugs on the market are from natural origin; these authors stated that, out of the 1,328 new chemical entities approved as drugs between 1981 and 2016, only 359 were purely of synthetic origin
We focused on strategies based on synthetic biology and syntheses that allow reaching industrial scale supply
Natural origin can have different definitions, and these authors accounted for three categories: unaltered natural products; defined mixture of natural products (NP) and natural product derivatives isolated from plants or other living organisms as fungi, sponges, lichens, or microorganisms; and products modified by medicinal chemistry
Summary
Like the updated survey from Newman and Cragg (2016), pointed to the fact that many drugs on the market are from natural origin; these authors stated that, out of the 1,328 new chemical entities approved as drugs between 1981 and 2016, only 359 were purely of synthetic origin. If the collected species are not properly reported following the correct taxonomy, the harvest might be even more difficult to reproduce: thereby, a table of correspondence between the names mentioned in this review (and used in the articles of origin) and the accepted plant species names is provided in the supplementary data (Table S1) Another type of limitation is related with the fact that groups performing bioguided discovery of new actives are often confronted with similar problems: (a) the active extracts, once fractionated, do not maintain the level of activity; (b) the whole long and difficult isolation process leads to a molecule that is mundane or known for decades; (c) the final product quantity in the remaining active fraction is too small to hope for a structure elucidation; (d) going back to the location of origin, the same plant population is not found anymore or if the plant is found, the same extraction treatment led to an apparent lack of active fraction(s) on the same target. Such approaches (phenotype screening and reverse pharmacology) would require disease models that are far from being the current available systems
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