Novel, Potent and Drug-like Scaffolds Obtained from a Synthetic Biology Approach in Yeast

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Jens Klein, Thomas stergaard Tange, Fanny Delegrange, Jutta Heim

Evolva S.A., Switzerland

Background: Molecular obesity, i.e. the tendency to generate more potent compounds by increasing their MW and lipophilicity, is one of the main reasons for problems in absorption, distribution, metabolism, excretion, toxicity (ADMET) and costly failures in drug development. Therefore, medicinal chemists nowadays increasingly use a range of physico-chemical parameters to select the most suitable chemical structures for lead optimisation. Based on their co-evolution with target proteins, natural products exhibit many favourable physicochemical, structural and shape properties, but often also suffer from the problem of molecular obesity. In this study, properties of compounds obtained by Synthetic Biology are compared to chemical screening collections on one side and natural products on the other. Experimental approach: Saccharomyces cerevisiae (baker’s yeast) was transformed with artificial chromosomes, containing genes of a number of metabolic pathways absent in yeast, as well as cDNA libraries from natural products producing sources. In addition, the yeast was engineered to express a functional assay which interacts with the chemicals produced from the YAC-encoded enzymes and confers the producing yeast a survival advantage. Chemicals produced by surviving yeasts were isolated and their structures and biological properties determined. Results: 75% of the molecules found were new, i.e. previously not described elsewhere. 20% of the compounds showed novel and very diverse scaffold structures. In terms of size, the described synthetic biology approach resulted in mainly fragment- to scaffold-sized molecules which retained excellent biological activity. Their structural and physico-chemical properties are in line with established rules of drug-likeness and exhibit very favourable shape complexity. Compounds obtained by Synthetic Biology therefore fit perfectly into the pharmaceutical industry drug discovery value chain and represent valuable, alternative and complementary sources for further lead optimisation.