title: Alkaloids as inhibitors of malate synthase from Paracoccidioides spp.: receptor-ligand interaction-based virtual screening and molecular docking studies, antifungal activity, and the adhesion process.
abstract: Paracoccidioides is the agent of paracoccidioidomycosis. Malate synthase plays a crucial role in the pathogenicity and virulence of various fungi, such as those that are human pathogens. Thus, an inhibitor of this enzyme may be used as a powerful antifungal without side effects in patients once these enzymes are absent in humans. Here, we searched for compounds with inhibitory capacity against the malate synthase of Paracoccidioides species (PbMLS). The three-dimensional (3D) structure of PbMLS was determined using the I-TASSER server. Compounds were selected from the ZINC database. Based on the mechanism underlying the interaction of the compounds with PbMLS, it was possible to identify β-carboline moiety as a standard key structure. The compounds with β-carboline moiety that are available in our laboratories were investigated. A total of nine alkaloid compounds were selected. The primary mechanisms of interaction of the alkaloid compounds in the binding pocket of PbMLS were identified and compared with the mechanism of interaction of acetyl coenzyme A (acetyl-CoA). We discovered that the amphipathic nature of the compounds, concomitant with the presence of β-carboline moiety, was crucial for their stability in the binding pocket of PbMLS. In addition, the importance of a critical balance of the polar and nonpolar contacts of the compounds in this region was observed. Four β-carboline alkaloid compounds showed the ability to inhibit recombinant PbMLS (PbMLSr) activity, Paracoccidioides species growth, and adhesion of the fungus and PbMLSr to the extracellular matrix components. The cytotoxicity of the alkaloids was also evaluated.
authors.affiliation: Núcleo Colaborativo de BioSistemas, Regional Jataí, Universidade Federal de Goiás, Jataí, Goiás, Brazil.
authors.forename: Fausto Guimaraes
authors.initials: FG
authors.lastname: Costa
authors.affiliation: Laboratório de Biologia Molecular, Instituto de Ciências Biológicas, Universidade Federal de Goiás, Goiânia, Goiás, Brazil.
authors.forename: Benedito Rodrigues da Silva
authors.initials: BR
authors.lastname: Neto
authors.affiliation: Núcleo Colaborativo de BioSistemas, Regional Jataí, Universidade Federal de Goiás, Jataí, Goiás, Brazil.
authors.forename: Ricardo Lemes
authors.initials: RL
authors.lastname: Gonçalves
authors.affiliation: Núcleo Colaborativo de BioSistemas, Regional Jataí, Universidade Federal de Goiás, Jataí, Goiás, Brazil.
authors.forename: Roosevelt Alves
authors.initials: RA
authors.lastname: da Silva
authors.affiliation: Laboratório de Produtos Naturais, Instituto de Química, Universidade Federal de Goiás, Goiânia, Goiás, Brazil.
authors.forename: Cecília Maria Alves
authors.initials: CM
authors.lastname: de Oliveira
authors.affiliation: Laboratório de Produtos Naturais, Instituto de Química, Universidade Federal de Goiás, Goiânia, Goiás, Brazil.
authors.forename: Lucília
authors.initials: L
authors.lastname: Kato
authors.affiliation: Laboratório de Produtos Naturais, Instituto de Química, Universidade Federal de Goiás, Goiânia, Goiás, Brazil.
authors.forename: Carla Dos Santos
authors.initials: Cdos S
authors.lastname: Freitas
authors.affiliation: Laboratório de Micologia Clínica, Universidade Estadual Júlio de Mesquita Melo, Araraquara, São Paulo, Brazil.
authors.forename: Maria José Soares Mendes
authors.initials: MJ
authors.lastname: Giannini
authors.affiliation: Laboratório de Micologia Clínica, Universidade Estadual Júlio de Mesquita Melo, Araraquara, São Paulo, Brazil.
authors.forename: Julhiany de Fátima
authors.initials: Jde F
authors.lastname: da Silva
authors.affiliation: Laboratório de Biologia Molecular, Instituto de Ciências Biológicas, Universidade Federal de Goiás, Goiânia, Goiás, Brazil.
authors.forename: Célia Maria de Almeida
authors.initials: CM
authors.lastname: Soares
authors.affiliation: Laboratório de Biologia Molecular, Instituto de Ciências Biológicas, Universidade Federal de Goiás, Goiânia, Goiás, Brazil maristelaufg@gmail.com.
authors.forename: Maristela
authors.initials: M
authors.lastname: Pereira
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D008292:Malate Synthase / Q000037:antagonists & inhibitors*; D010228:Paracoccidioides / Q000201:enzymology*
chemical_list: D000470:Alkaloids; D000935:Antifungal Agents; D008292:Malate Synthase