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Synthetic and Medicinal Chemistry

The early days of drug discovery and development were lonely: scientists in the 19th century made discoveries often driven by serendipity. Although fortuitous findings continue to happen, we currently rely on the synergistic collaboration across the organic and medicinal chemistry areas for accelerating the rational identification and design of lead compounds.

This collection showcases some of the most recent advances in the multidisciplinary field of discovery and development of bioactive compounds published in Nature Communications. The Medicinal Chemistry tab highlights additions to the med. chem. toolbox. Under Catalysis for Bioactive Compounds we acknowledge advances in homogeneous catalysis that open the door to obtaining bioactive compounds in higher quantity, quality and/or purity. Tying in with that, the Total Synthesis section contains reports on the complete chemical synthesis of natural products, still one of the best sources of drugs and drug leads. Last but not least, the Drug Biosynthesis section showcases some of the most recent discoveries of how Nature synthesizes bioactive compounds and how biocatalytic machinery can be exploited for chemical synthesis.

This collection will be regularly updated with studies published in Nature Communications that advance the field of medicinal and synthetic chemistry.

Pleuromutilin derivatives are potent antibacterial drugs obtained from Basidiomycete fungi. Here, the authors report the genetic characterisation of the steps involved in pleuromutilin biosynthesis through heterologous expression and generate a semi-synthetic pleuromutilin derivative with enhanced antibiotic activity.

Article | open | | Nature Communications

Tuberculosis (TB) remains one of the world’s deadliest communicable diseases, novel anti-TB agents are urgently needed due to severe drug resistance and the co-epidemic of TB/HIV. Here, the authors show that anti-mycobacterial ilamycin congeners bearing unusual structural units possess extremely potent anti-tuberculosis activities.

Article | open | | Nature Communications

Metalloproteinase inhibitors are leads for drug development, but their biosynthetic pathways are often unknown. Here the authors show that the acyl branched warhead of actinonin and matlystatins derives from an ethylmalonyl-CoA-like pathway and the structural diversity of matlystatins is due to the activity of a decarboxylase-dehydrogenase enzyme.

Article | open | | Nature Communications

Optimizing an enzyme usually requires testing thousands of variants, thus consuming large amounts of material and time. Here, the authors present a method that allows for measuring two different activities of the same enzyme simultaneously instead of doing two consecutive rounds of screening.

Article | open | | Nature Communications

Cyclic peptide macrocycles are promising anti-cancer and antimicrobial molecules. Here, the authors characterize the structure and catalytic mechanism of the prolyl oligopeptidase B from Basidiomycete fungi, showing that its dual macrocyclase-peptidase activity is crucial for amatoxin macrocyclization.

Article | open | | Nature Communications

Glyoxalase I converts toxic methylglyoxal to a thioester. Here the authors report a synthetic analogue capable of enantioselectively converting alpha-keto aldehydes to thioesters via formation of a hemithioacetal, giving access to both enantiomers of a range of alpha-hydroxy thioesters.

Article | open | | Nature Communications