Download Why Natural Products? Natural products remain the best sources of

Why Natural Products?
Natural products remain the best sources of drugs and drug leads
Natural products remain the best sources of drugs and drug leads, and this remains true today
despite the fact that many pharmaceutical companies have deemphasized natural products
research in favor of HTP screening of combinatorial libraries during the past 2 decades. From
1940s to date, 131 (74.8%) out of 175 small molecule anticancer drugs are natural productbased/inspired, with 85 (48.6%) being either natural products or derived therefrom. From 1981
to date, 79 (80%) out of 99 small molecule anticancer drugs are natural product-based/inspired,
with 53 (53%) being either natural products or derived therefrom. Among the 20 approved small
molecule New Chemical Entities (NCEs) in 2010, a half of them are natural products.
Natural products possess enormous structural and chemical diversity that is unsurpassed by
any synthetic libraries. About 40% of the chemical scaffolds found in natural products are
absent in today’s medicinal chemistry repertoire. Based on various chemical properties,
combinatorial compounds occupy a much smaller area in molecular space than natural
products. Although combinatorial compounds occupy a well-defined area, natural products and
drugs occupy all of this space as well as additional volumes. Most importantly, natural products
are evolutionarily optimized as drug-like molecules. This is evident upon realization that natural
products and drugs occupy approximately the same molecular space.
Natural products represent the richest source of novel molecular scaffolds and chemistry. No
one can predict, in advance, the details of how a small molecule will interact with the myriad of
targets that we now know drive fundamental biological processes. The history of natural product
discovery is full of remarkable stories of how the discovery of a natural product profoundly
impacted advances in biology and therapy. For instance, Taxol's impact on tubulin
polymerization, and correlation to antitumor action or rapamycin's binding to mTOR and the
ramifications of mTOR inhibitors could never be predicted a priori. The discovery of new natural
products promises significant advances not only in chemistry, but also, biochemistry and
medicine.
Natural products are significantly underrepresented in current small molecule libraries
In spite of the great success of natural products in the history of drug discovery, natural
products are significantly underrepresented in current small molecule libraries. Challenges of
natural products in drug discovery and development include (i) extremely low yields, (ii) limited
supply, (iii) complex structures posing enormous difficulty for structural modifications, and (iv)
complex structures precluding practical synthesis. These difficulties lead to the pharmaceutical
industry to embrace new technologies in the past two decades, particularly combinatorial
chemistry, at the detriment to interest in natural product discovery.
Microbial natural products as preferred sources of new drugs and drug leads
Microbial natural products have several intrinsic properties favoring their consideration in drug
discovery and development. Microbial natural products can be produced by large-scale
fermentation. Microorganisms can be engineered to overproduce the desired natural products
hence to solving the supply bottleneck. Microbial natural product analogues can be produced
by metabolic pathway engineering, thereby providing a focused library for structure-activityrelationship studies. The vast, untapped, ecological biodiversity of microbes holds great
promise for the discovery of novel natural products, thereby improving the odds of finding novel
drug leads.
The exponential growth in cloning and characterization of natural product biosynthetic
machinery from microbes in the last two decades has unveiled unprecedented molecular
insights into natural product biosynthesis, including the observation that genes for natural
product biosynthesis are clustered in the microbial genome and that variations of a few common
biosynthetic machineries can account for vast structural diversity observed for natural products.
These findings have fundamentally changed the landscape of natural product research by
enabling the revision of known natural product structures, the prediction of yet-to-be isolated
novel compounds on the basis of gene sequences, and the systematic generation of “unnatural”
natural products by manipulating genes governing their biosynthesis (also known as
combinatorial biosynthesis).
Whole genome sequencing has revealed far more biosynthetic gene clusters than actual
metabolites currently known for a given organism, suggesting that the biosynthetic potential for
natural products in microorganisms is greatly under-explored by traditional natural product
discovery methods. Among the Streptomyces whose genomes have been sequenced, every
one of them has the potential to produce up to 30 natural products on average, and this
optimism has already translated into the discovery of new natural products by fermentation
optimization from strains that otherwise were not previously known as natural product
producers.
Only 1% of the microbial community has been estimated to be cultivated in the lab, implying that
the vast biodiversity of microbial natural products remains underappreciated. Emerging new
cultivating techniques, culture-independent methods by expressing gene clusters in model
heterologous hosts, and diligent effort and innovative approaches in novel microbial strain
collection, identification, and classification have started to permit access to these previously
inaccessible natural product resources.
The future of microbial natural product drug discovery and development remains bright. (i)
Advances in DNA sequencing will greatly facilitate genome sequencing and genomics-based
natural products discovery. (ii) Advances in DNA synthesis and synthetic biology will greatly
facilitate natural product pathway reconstruction, engineering, and expression in model or
industrial hosts for natural product production. (iii) Advances in HTS will further enable rapid
screening of natural product libraries for an ever broader range of biological application. (iv)
Advances in isolation technologies, analytic methods, automatic robotics, and database
management will greatly facilitate natural products library construction. (v) Environmental
concerns will further favor bio-based natural products drug discovery and development
processes, i.e., fermentation, metabolic pathway engineering, and renewable resources.