Natural products (NPs) are an invaluable source of inspiration in drug design and development and have long been regarded as “Nature’s medicine chest” providing invaluable platforms for developing front-line drugs. 65% of the 1211 small-molecule new drugs approved between 1981-2014 were “inspired by” natural products. Having evolved over several millennia to acquire specific ligand-protein binding motifs, NP structures cover a wide range of biologically relevant chemical space that cannot be efficiently explored by synthetic compounds in commercially available screening libraries. These privileged scaffolds serve as important, biologically pre-validated platforms for the design of compound libraries in the search for new drug candidates. NPs favour inclusion of aliphatic over aromatic rings, as well as more sp3-hybridised bridgehead atoms and chiral centres than synthetic small molecules. As the clinical success of drug candidates is directly correlated to three-dimensionality of the molecules, NPs clearly possess an advantageous structural foundation over synthetic small molecules in the development of drug candidates. The neglect of chirality has been recognized as a key deficiency of contemporary drug discovery methodology. However, the structural complexity, toxicity, and unfavourable pharmacokinetics (PKs) often associated with NPs can limit their clinical potential, and as such, structural modification is often required. To this end, many leading chemists are not only targeting bioactive NPs, but also libraries of structurally related compounds for biological evaluation. The core scaffold of NPs and their analogue libraries may therefore be considered “privileged” since contemporary use of the term typically refers to multiple compounds with the same core scaffold possessing bioactivity. Herein advances in the use of NP-derived privileged scaffolds in drug discovery are described. This lecture will also showcase the synthesis of bioactive NPs and peptides from our own research as examples of unexplored novel structural chemotypes.

Natural product derived privileged scaffolds in drug discovery

2019 Fall National Meeting

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