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PUBLISHED ONLINE: 25 APRIL 2016|DOI: http://dx.doi.org/10.1038/nchem.2479
Web End =10.1038/NCHEM.2479
Counting on natural products for drug design
Natural products and their intricate molecular frameworks oer medicinal chemists a range of uncharted chemo-types for the discovery of chemical probes and drugs17.
Natural products oen feature biologically relevant molecular scaffolds and pharmacophore patterns that have evolved as preferred ligandprotein binding motifs812. Therefore, natural products have long been explored as invaluable sources of inspiration for drug design, with particular eectiveness in cancerous and infectious diseases1316.For example, rosuvastatin, a blockbuster drug for the treatment of high cholesterol, mimics the pharmacophore of the natural product mevastatin from the fungus Penicillium citrinum but contains fewer chiral centres (Fig.1). Focused natural-product-inspired compound libraries may transfer, at least in part, pharmacologically relevant features to synthetically more tractable small molecules, thereby potentially improving the biological activity of these synthetic small molecules. Thus, it is no surprise to see pharmaceutical drug discovery programmes benetting from the incorporation of natural-product-derived fragments into development pipelines. An analysis of drugs that have been approved by the US Food and Drug Administration since 1939 reveals the persistent use of natural-product-derived fragments in medicinal chemistry (Fig.2b). We anticipate molecular design in chemical biology and medicinal chemistry to be further propelled by systematically exploring the chemical space of natural products17,18. Recent technological advances support this optimistic view, specically for the discovery of biosynthetic gene clusters producing bioactive secondary metabolites19, the development of bioinformatic methods for identifying such biosynthetic gene clusters in genome sequences and predicting the chemical structures of their products20, and the synthesis of natural products and derivatives through the manipulation of biosynthetic enzymes21.
Natural products are oen perceived as chemically complex and diering from synthetic drug-like molecules in many regards22.
Pioneering studies in the early 2000s revealed that these products contain a much larger fraction of sp3-hybridized bridgehead atoms and chiral centres compared with synthetic small molecules1,23.
Natural products also present a lower nitrogen but higher oxygen content on average. Nature apparently favours aliphatic over aromatic rings, with only 38% of the known natural products containing arene systems. Approximately 50% of the structurally resolved natural products in the Dictionary of Natural Products database do not have synthetic counterparts, and only approximately 20% of the
Tiago Rodrigues1, Daniel Reker1,...