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
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2015-09
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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 -carboline moiety as a standard key structure. The
compounds with -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 -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 -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.
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COSTA, Fausto Guimaraes et al. 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. Antimicrobial Agents and Chemotherapy, Washington, v. 59, n. 9, p. 5581-5594, Sept. 2015.