Journal
MEDCHEMCOMM
Volume 3, Issue 8, Pages 854-865Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c2md00316c
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Natural products are an unsurpassed source of lead structures for drug discovery. However, these molecules, many of which fall into the beyond-rule-of-5 chemical space, are often difficult to optimize by chemical means because of their complex structures. Biosynthetic engineering of the producing host organism offers an important tool for the modification of complex natural products, leading to analogues which are unattainable by chemical semisynthesis. This review describes the current role of natural products in lead generation and the principles behind biosynthetic medicinal chemistry. It then goes on to describe five distinct drugs - salinosporamide, geldanamycin, FK506, rapamycin and epothilone - to exemplify how biosynthetic engineering approaches have contributed to the advancement of natural product clinical candidates.
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