This work evaluated new potential inhibitors of the enzyme homoserine dehydrogenase (HSD) of Paracoccidioides brasiliensis, one of the etiological agents of paracoccidioidomycosis. The tertiary structure of the protein bonded to the analogue NAD, and L-homoserine was modeled by homology. The model with the best output was subjected to gradient minimization, redocking, and molecular dynamics simulation. Virtual screening simulations with 187,841 molecules purchasable from the Zinc database were performed. After the screenings, 14 molecules were selected and analyzed by the use of absorption, distribution, metabolism, excretion, and toxicity criteria, resulting in four compounds for in vitro assays. The molecules HS1 and HS2 were promising, exhibiting MICs of 64 and 32 g · ml Ϫ1 , respectively, for the Pb18 isolate of P. brasilensis, 64 g · ml Ϫ1 for two isolates of P. lutzii, and also synergy with itraconazole. The application of these molecules to 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.
The viral cathepsin from Bombyx mori Nucleopolyhedrosis virus (BmNPV-Cath) is a broad-spectrum protease that participates in the horizontal transmission of this virus in silkworm by facilitating solubilization of the integument of infected caterpillars. When a B. mori farm is attacked by Bombyx mori Nucleopolyhedrosis virus (BmNPV), there are significant sericultural losses because no drugs or therapies are available. In this work, the structure of viral cathepsin BmNPV-Cath was used as a target for virtual screening simulations, aiming to identify potential molecules that could be used to treat the infection. Virtual screening of the Natural Products library from the Zinc Database selected four molecules. Theoretical calculations of ΔG by the molecular mechanics Poisson-Boltzmann surface analysis (MM-PBSA) method indicated that the molecule Zinc12888007 (Bm5) would have high affinity for the enzyme. The in vivo infection models of B. mori caterpillars with BmNPV showed that treatment with a dose of 100 μg Bm5 dissolved in Pluronic-F127 0.02% was able to reduce the mortality of caterpillars in 22.6%, however, it did not impede the liquefaction of dead bodies. Our results suggest a role of BmNPV-Cath in generating a pool of amino acids necessary for viral replication and indicate a mechanism to be exploited in the search for treatments for grasserie disease of the silkworm.
The herbicide diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea) is used in many agricultural crops and non-crop areas worldwide,
leading to the pollution of the aquatic environment by soil leaching. White rot fungi and its lignin modifying enzymes, peroxidases
and laccases, are responsible for its degradation. Therefore, it is of interest to explore the potential use of Ceriporiopsis subvermispora
laccase (CersuLac1) in the biotransformation of this herbicide by using its enzyme laccase. However, the structure of laccase from
Ceriporiopsis subvermispora is still unknown. Hence, a model of laccase was constructed using homology modeling. The model was
further used to dock p-methylbenzoate in the presence of four copper ions to analyze molecular basis of its binding and interaction.
The ligand-protein interaction is stereo-chemically favorable in nature. The presence of the single protonated Lys457 was necessary
for catalysis, being coordinated by a cupper ion. The best pose of diuron on CersuLac1 has a theoretical Ki of 2.91 mM. This is
comparable to the KM values for laccases from other organisms with similar compounds. Thus, we document the insights for the
potential use of laccase from Ceriporiopsis subvermispora in the biotransfrormation of diuron.
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