Computational repositioning of bioactive compounds from large chemogenomic screens: identification of conserved druggable modules between yeasts and trypanosomes

MERCEDES DIDIER GARNHAM; LANDABURU, LIONEL URÁN; EMIR SALAS SARDUY; FERNAN AGUERO

Mendoza

Congreso; XI Congreso SAP 2022; 2022

Sociedad Argentina de Protozología

Detailed characterization of the cellular response to chemicals is fundamental to understand the mechanism of action of drugs. One strategy to do this is to analyze the growth capacity (fitness) of gene mutants exposed to different drugs. Recently, a number of genome‐wide fitness profiling assays were performed on Saccharomyces cerevisiae. These chemical-genomics screens were based on whole-genome collections of heterozygous and homozygous deletions and quantified the growth fitness of each strain in the presence of different chemicals. Now, several such chemogenomic datasets are available, providing a rich source of pharmacogenomic associations between drugs and genes (“druggable modules”). In contrast, in trypanosomes, pharmacogenomic associations are scarce; hence these yeast chemogenomic screens may serve as good starting points to guide repurposing opportunities. The aim of this project is the curation and standardization of yeast-based chemogenomic assays from published studies, and the development of an orthology mapping pipeline. Using this pipeline to find conserved druggable modules between yeasts and T. cruzi, we obtained 271.955 gene-drug interactions, with a set of 5.811 unique genes and 2.935 unique drugs. Further filters were applied to each set. For drugs, filters were applied to retain compounds that are drug-like, novel, commercially available, and with low potential promiscuity. For genes, we selected those that have T. brucei orthologs with significant fitness phenotypes when knocked down (through an orthology mapping between T. cruzi genes and T. brucei whole-genome RNAi essentiality assays described in Alsford et al, 2011). After standardization and filtering we obtained a library of 174 compounds, associated with 66 candidate protein targets in T. cruzi. We purchased 22 of those compounds and assessed their antiparasitic activity in vitro. This step allows us to validate the strategy and to select novel drug candidates to treat Chagas disease.