title: Identification of New Antifungal Compounds Targeting Thioredoxin Reductase of Paracoccidioides Genus.
abstract: The prevalence of invasive fungal infections worldwide has increased in the last decades. The development of specific drugs targeting pathogenic fungi without producing collateral damage to mammalian cells is a daunting pharmacological challenge. Indeed, many of the toxicities and drug interactions observed with contemporary antifungal therapies can be attributed to "nonselective" interactions with enzymes or cell membrane systems found in mammalian host cells. A computer-aided screening strategy against the TRR1 protein of Paracoccidioides lutzii is presented here. Initially, a bank of commercially available compounds from Life Chemicals provider was docked to model by virtual screening simulations. The small molecules that interact with the model were ranked and, among the best hits, twelve compounds out of 3,000 commercially-available candidates were selected. These molecules were synthesized for validation and in vitro antifungal activity assays for Paracoccidioides lutzii and P. brasiliensis were performed. From 12 molecules tested, 3 harbor inhibitory activity in antifungal assays against the two pathogenic fungi. Corroborating these findings, the molecules have inhibitory activity against the purified recombinant enzyme TRR1 in biochemical assays. Therefore, a rational combination of molecular modeling simulations and virtual screening of new drugs has provided a cost-effective solution to an early-stage medicinal challenge. These results provide a promising technique to the development of new and innovative drugs.
authors.affiliation: Department of Biology, University of Mato Grosso State - UNEMAT, Nova Xavantina, Mato Grosso, Brazil.
authors.forename: Ana Karina Rodrigues
authors.initials: AK
authors.lastname: Abadio
authors.affiliation: Department of Clinical Analysis and Biomedicine, State University of Maringá, Maringá, Paraná, Brazil.
authors.forename: Erika Seki
authors.initials: ES
authors.lastname: Kioshima
authors.affiliation: LORIA, Lorraine University, Nancy, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Leroux
authors.affiliation: Embrapa - Genetic Resources and Biotechnology, Brasília, Distrito Federal, Brazil.
authors.forename: Natalia Florêncio
authors.initials: NF
authors.lastname: Martins
authors.affiliation: LORIA, Lorraine University, Nancy, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Maigret
authors.affiliation: Department of Cellular Biology, University of Brasília - UnB, Brasília, Distrito Federal, Brazil.
authors.forename: Maria Sueli Soares
authors.initials: MS
authors.lastname: Felipe
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D001681:Biological Assay; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D057075:Enzyme Assays; D004791:Enzyme Inhibitors / Q000032:analysis / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010228:Paracoccidioides / Q000187:drug effects / Q000201:enzymology* / Q000302:isolation & purification; D011994:Recombinant Proteins / Q000378:metabolism; D054852:Small Molecule Libraries / Q000032:analysis / Q000494:pharmacology; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D013880:Thioredoxin-Disulfide Reductase