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

ABSTRACTParacoccidioidesis 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 ofParacoccidioidesspecies (PbMLS). The three-dimensional (3D) structure ofPbMLS was determined using the I-TASSER server. Compounds were selected from the ZINC database. Based on the mechanism underlying the interaction of the compounds withPbMLS, 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 ofPbMLS 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 ofPbMLS. 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 recombinantPbMLS (PbMLSr) activity,Paracoccidioidesspecies growth, and adhesion of the fungus andPbMLSr to the extracellular matrix components. The cytotoxicity of the alkaloids was also evaluated.