| Autor: |
Tartari JC; Department of Technology, Universidade Estadual de Maringá, Umuarama, PR 87501-390, Brazil., Khan A; Department of Technology, Universidade Estadual de Maringá, Umuarama, PR 87501-390, Brazil., da Silva Andrade JG; Department of Technology, Universidade Estadual de Maringá, Umuarama, PR 87501-390, Brazil., Vilugron Rodrigues FA; Department of Clinical Analysis, Universidade Estadual de Maringá, Maringá, PR 87020-900, Brazil., Alves Bueno PS; Department of Biochemistry, Universidade Estadual de Maringá, Maringá, PR 87020-900, Brazil., Souza Lima D; Department of Technology, Universidade Estadual de Maringá, Umuarama, PR 87501-390, Brazil., Canduri F; São Carlos Institute of Chemistry, Universidade de São Paulo, São Carlos, SP 13566-590, Brazil., Freitas Gauze G; Department of Chemistry, Universidade Estadual de Maringá, Maringá, PR 87020-900, Brazil., Kioshima ÉS; Department of Clinical Analysis, Universidade Estadual de Maringá, Maringá, PR 87020-900, Brazil., Vicente Seixas FA; Department of Technology, Universidade Estadual de Maringá, Umuarama, PR 87501-390, Brazil. |
| Abstrakt: |
Aim: To search for potential inhibitors to homoserine dehydrogenase (HSD) in Paracoccidioides brasiliensis the causative agent of paracoccidioidomycosis, an infection with a high mortality rate in Brazil. Materials & methods: The enzyme was modeled and used in the virtual screening of the compounds. The library was first screened by the Autodock, in which 66 molecules were better ranked than substrate, and then, also evaluated by the Molegro and Gold programs. Results: The HS23 and HS87 molecules were selected in common by the three programs, and ADME/Tox evaluation indicates they are not toxic. The molecular dynamics of Pb HSD bonded to ligands showed stable complexes until 50 ns. To validate the results, compounds were purchased for assays of minimum inhibitory concentration (MIC), minimum fungicidal concentration (MFC), synergic profile with Amphotericin B (AmB) and cytotoxicity. The two molecules presented MIC of 32 μg/ml and MFC of 64 μg/ml against the P. brasiliensis (strain Pb18). They also showed synergistic activity with AmB and a lack of toxicity against Hela and Vero cell lines. Conclusion: These results suggest that the HS23 and HS87 are promising candidates as Pb HSD inhibitors and may be used as hits for the development of new drugs against paracoccidioidomycosis. |
