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

Abstract

Paracoccidioidomycosis (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.

Communicated by Ramaswamy H. Sarma

Keywords:

• Virtual screening
• molecular dynamics
• Paracoccidioides spp.
• methylcitrate synthase
• inhibitors

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was performed at Universidade Federal de Goiás supported by MCTI/CNPq (Ministério da Ciência e Tecnologia/Conselho Nacional de Desenvolvimento Científico e Tecnológico), FNDCT (Fundo Nacional de Desenvolvimento Científico e Tecnológico), FAPEG (Fundação de Amparo à Pesquisa do Estado de Goiás), CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/Finance Code 001), FINEP (Financiadora de Estudos e Projetos), PRONEX (Programa de Apoio a Núcleos de Excelência), INCT-IPH (Instituto Nacional de Ciência e Tecnologia de Estratégias de Interação Patógeno-Hospedeiro) and FAPEG NEWTON programme (201510267000251). Work of MB was supported by the MRC-Newton programme (Grant No. MR/N017528/1).