| Autor: |
Tartari, Jovana Chiapetti, Khan, Asif, da Silva Andrade, João Gabriel, Vilugron Rodrigues, Francielli Abigail, Alves Bueno, Paulo Sérgio, Souza Lima, Diego de, Canduri, Fernanda, Freitas Gauze, Gisele de, Kioshima, Érika Seki, Vicente Seixas, Flavio Augusto |
| Zdroj: |
Future Microbiology; November 2024, Vol. 19 Issue: 17 p1475-1488, 14p |
| Abstrakt: |
Aim:To search for potential inhibitors to homoserine dehydrogenase (HSD) in Paracoccidioides brasiliensisthe 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 PbHSD 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 PbHSD inhibitors and may be used as hits for the development of new drugs against paracoccidioidomycosis. |
| Databáze: |
Supplemental Index |
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