title: Yeast synthetic biology platform generates novel chemical structures as scaffolds for drug discovery.
abstract: Synthetic biology has been heralded as a new bioengineering platform for the production of bulk and specialty chemicals, drugs, and fuels. Here, we report for the first time a series of 74 novel compounds produced using a combinatorial genetics approach in baker's yeast. Based on the concept of "coevolution" with target proteins in an intracellular primary survival assay, the identified, mostly scaffold-sized (200-350 MW) compounds, which displayed excellent biological activity, can be considered as prevalidated hits. Of the molecules found, >75% have not been described previously; 20% of the compounds exhibit novel scaffolds. Their structural and physicochemical properties comply with established rules of drug- and fragment-likeness and exhibit increased structural complexities compared to synthetically produced fragments. In summary, the synthetic biology approach described here represents a completely new, complementary strategy for hit and early lead identification that can be easily integrated into the existing drug discovery process.
authors.affiliation: Evolva SA, Duggingerstrasse 23, CH-4153 Reinach, Switzerland.
authors.forename: Jens
authors.initials: J
authors.lastname: Klein
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Heal
authors.forename: William D O
authors.initials: WD
authors.lastname: Hamilton
authors.forename: Thiamo
authors.initials: T
authors.lastname: Boussemghoune
authors.forename: Thomas Østergaard
authors.initials: TØ
authors.lastname: Tange
authors.forename: Fanny
authors.initials: F
authors.lastname: Delegrange
authors.forename: Georg
authors.initials: G
authors.lastname: Jaeschke
authors.forename: Anaëlle
authors.initials: A
authors.lastname: Hatsch
authors.forename: Jutta
authors.initials: J
authors.lastname: Heim
mesh_terms: D055808:Drug Discovery / Q000379:methods*; D008958:Models, Molecular; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism; D058615:Synthetic Biology / Q000379:methods*; D015003:Yeasts / Q000235:genetics / Q000378:metabolism*
chemical_list: D054852:Small Molecule Libraries
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