Natural Products Drug Discovery

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Classical natural product chemistry methodologies enabled a vast array of bioactive secondary metabolites from terrestrial and marine sources to be discovered. Many of these natural products have gone on to become current drug candidates. An advance in technology and sensitive instrumentation for the rapid identification of novel bioactive natural products and structure elucidation continues to improve the natural product discovery process. Chemistry has indeed revolutionized the development of novel active chemical leads resulting in the synthesis of structural analogues. Natural products constitute a key source of pharmacologically active ingredients in a variety of novel agents with therapeutic potential in a wide range of diseases. Pharmaceuticals containing natural products or compounds derived from natural product scaffolds or templates have to undergo the same stringent approval process as drugs obtained from purely synthetic origin.

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 product-based/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.