Targeting homoserine dehydrogenase from Paracoccidioides Genus against systemic fungal infections [PublishAheadOfPrint]

This work evaluated new potential inhibitors of the enzyme homoserine dehydrogenase (HSD) from Paracoccidioides brasiliensis, one of the etiological agent of paracoccidioidomycosis. The tertiary structure of the protein bonded to the analogue NAD and L-homoserine was modeled by homology. The best output model was subjected to gradient minimization, redocking and molecular dynamics. Virtual screening simulations with 187,841 purchasable molecules from the Zinc database were performed. After the screenings, 14 molecules were selected and analyzed by ADMETox criteria, resulting in four compounds for in vitro assays. The molecules HS1 and HS2 were promising, exhibiting MICs of 64 and 32 μg.mL^-1 respectively for the Pb18 isolate of P. brasilensis, 64 μg.mL^-1 for two isolates of P. lutzii and also synergy with itraconazole. The application of these molecules in human pathogenic fungi confirmed that the HSD enzyme may be used as a target for the development of drugs with specific action against paracoccidioidomycosis; moreover these compounds may serve as leads in the design of new antifungals.

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