A structure-based approach for the discovery of inhibitors against methylcitrate synthase of Paracoccidioides lutzii

dc.creatorLima, Raisa Melo
dc.creatorSilva, Kleber Santiago Freitas e
dc.creatorSilva, Lívia do Carmo
dc.creatorRibeiro, Jean Francisco Rosa
dc.creatorNeves, Bruno Junior
dc.creatorBrock, Matthias
dc.creatorSoares, Célia Maria de Almeida
dc.creatorSilva, Roosevelt Alves da
dc.creatorPereira, Maristela
dc.date.accessioned2024-09-12T14:26:43Z
dc.date.available2024-09-12T14:26:43Z
dc.date.issued2021
dc.description.abstractParacoccidioidomycosis (PCM) is a systemic mycosis, endemic in Latin America, caused by fungi of the genus Paracoccidioides. The treatment of PCM is complex, requiring a long treatment period, which often results in serious side effects. The aim of this study was to screen for inhibitors of a specific target of the fungus that is absent in humans. Methylcitrate synthase (MCS) is a unique enzyme of microorganisms and is responsible for the synthesis of methylcitrate at the beginning of the propionate degradation pathway. This pathway is essential for several microorganisms, since the accumulation of propionyl-CoA can impair virulence and prevent the development of the pathogen. We performed the modeling and molecular dynamics of the structure of Paracoccidioides lutzii MCS (PlMCS) and performed a virtual screening on 89,415 compounds against the active site of the enzyme. The compounds were selected according to the affinity and efficiency criteria of in vitro tests. Six compounds were able to inhibit the enzymatic activity of recombinant PlMCS but only the compound ZINC08964784 showed fungistatic and fungicidal activity against Paracoccidioides spp. cells. The analysis of the interaction profile of this compound with PlMCS showed its effectiveness in terms of specificity and stability when compared to the substrate (propionyl-CoA) of the enzyme. In addition, this compound did not show cytotoxicity in mammalian cells, with an excellent selectivity index. Our results suggest that the compound ZINC08964784 may become a promising alternative antifungal against Paracoccidioides spp.
dc.identifier.citationLIMA, Raisa Melo et al. A structure-based approach for the discovery of inhibitors against methylcitrate synthase of Paracoccidioides lutzii. Journal of Biomolecular Structure & Dynamics, Guilderland, v. 40, n. 19, p. 9361-9373, 2021. DOI: 10.1080/07391102.2021.1930584. Disponível em: https://www.tandfonline.com/doi/full/10.1080/07391102.2021.1930584. Acesso em: 6 set. 2024.
dc.identifier.doi10.1080/07391102.2021.1930584
dc.identifier.issn0739-1102
dc.identifier.issne- 1538-0254
dc.identifier.urihttps://www.tandfonline.com/doi/full/10.1080/07391102.2021.1930584
dc.language.isoeng
dc.publisher.countryEstados unidos
dc.publisher.departmentFaculdade de Farmácia - FF (RMG)
dc.rightsAcesso Restrito
dc.subjectVirtual screening
dc.subjectMolecular dynamics
dc.subjectParacoccidioides spp.
dc.subjectMethylcitrate synthase
dc.subjectInhibitors
dc.titleA structure-based approach for the discovery of inhibitors against methylcitrate synthase of Paracoccidioides lutzii
dc.typeArtigo

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