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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. Several plants, human-pathogenic fungi, and bacteria utilize the glyoxylate cycle during host infection (1). The unique enzymes of this cycle are isocitrate lyase and malate synthase. This pathway has not been observed in mammals; therefore, this cycle has been identified as a potential target for the discovery of new drugs. Novel active molecules should shorten the duration of chemotherapy, prevent the development of resistance, and eliminate latent disease.In the human-pathogenic fungi from the genus Paracoccidioides, the malate synthase (PbMLS) participates in the glyoxylate pathway, which enables the fungus to assimilate two-carbon compounds, and in the allantoin degradation pathway associated with purine metabolism, which allows the fungus to use nitrogen compounds (2). PbMLS is localized in peroxisomes and on the cell surface and is secreted. In addition, PbMLS plays a role as an adhesin, mediating the adhesion and internalization of the fungus to host cells (3). PbMLS is regulated during the transition from mycelium to yeast (4) and in oxidative stress (5). However, an inhibitor to PbMLS has not yet been investigated.In recent years, virtual screening has become an accepted tool in drug discovery that has successfully been applied in a number of therapeutic programs, particularly at the lead discovery stage, during which high-throughput molecular docking can play an important r...

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