Proteomic identification of metabolic changes in Paracoccidioides brasiliensis induced by a nitroheteroarylchalcone.

Aim: To access the metabolic changes caused by a chalcone derivative (LabMol-75) through a proteomic approach. Methods: Proteomic analysis was performed after 9 h of Paracoccidioides brasiliensis yeast (Pb18) cell incubation with the LabMol-75 at MIC. The proteomic findings were validated through in vitro and in silico assays. Results: Exposure to the compound led to the downregulation of proteins associated with glycolysis and gluconeogenesis, ß-oxidation, the citrate cycle and the electron transport chain. Conclusion: LabMol-75 caused an energetic imbalance in the fungus metabolism and deep oxidative stress. Additionally, the in silico molecular docking approach pointed to this molecule as a putative competitive inhibitor of DHPS.

Identification of a new antifungal compound against isocitrate lyase of Paracoccidioides brasiliensis.

Aim: To perform virtual screening of compounds based on natural products targeting isocitrate lyase of Paracoccidioides brasiliensis. Materials & methods: Homology modeling and molecular dynamics simulations were applied in order to obtain conformational models for virtual screening. The selected hits were tested in vitro against enzymatic activity of ICL of the dimorphic fungus P. brasiliensis and growth of the Paracoccidioides spp. The cytotoxicity and selectivity index of the compounds were defined. Results & conclusion: Carboxamide, lactone and ß-carboline moieties were identified as interesting chemical groups for the design of new antifungal compounds. The compounds inhibited ICL of the dimorphic fungus P. brasiliensis activity. The compound 4559339 presented minimum inhibitory concentration of 7.3 µg/ml in P. brasiliensis with fungicidal effect at this concentration. Thus, a new potential antifungal against P. brasiliensis is proposed.

Computer-aided identification of novel anti-paracoccidioidomycosis compounds.

AIM: The shape-based virtual screening was used for the identification of new compounds anti-paracoccidioidomycosis (PCM). MATERIALS & METHODS: The study was performed according to the following steps: collection and curation of a dataset of quinolinyl N-oxide chalcones with anti-PCM activity, development and validation of shape-based models, application of the best model for virtual screening, and experimental validation. RESULTS & CONCLUSION: Among 31 computational hits, eight compounds showed potent antifungal activity and low cytotoxicity for mammalian cells. The checkerboard assay showed that most promising hit (compound 3) displayed additive effects with the antifungal cotrimoxazole and amphotericin B. Therefore, the shape-based virtual screening allowed us to discover promising compounds in prospective hit-to-lead optimization studies for tackling PCM.