Leishmaniasis is an infectious disease caused by parasites of the genus Leishmania and transmitted by the bite of a sand fly. To date, most available drugs for treatment are toxic and beyond the economic means of those affected by the disease. Protein disulfide isomerase (PDI) is a chaperone protein that plays a major role in the folding of newly synthesized proteins, specifically assisting in disulfide bond formation, breakage, or rearrangement in all non-native proteins. In previous work, we demonstrated that Leishmania major PDI (LmPDI) has an essential role in pathogen virulence. Furthermore, inhibition of LmPDI further blocked parasite infection in macrophages. In this study, we utilized a computer-aided approach to design a series of LmPDI inhibitors. Fragment-based virtual screening allowed for the understanding of the inhibitors’ modes of action on LmPDI active sites. The generated compounds obtained after multiple rounds of virtual screening were synthesized and significantly inhibited target LmPDI reductase activity and were shown to decrease in vitro parasite growth in human monocyte-derived macrophages. This novel cheminformatics and synthetic approach led to the identification of a new series of compounds that might be optimized into novel drugs, likely more specific and less toxic for the treatment of leishmaniasis.

利什曼病是一种由利什曼原虫属寄生虫引起的传染病，通过白蛉叮咬传播。迄今为止，大多数可用的治疗药物都是有毒的，超出了受该疾病影响的人的经济能力。蛋白质二硫键异构酶 (PDI) 是一种分子伴侣蛋白质，在新合成蛋白质的折叠中起主要作用，特别是协助所有非天然蛋白质中的二硫键形成、断裂或重排。在以前的工作中，我们证明了主要利什曼原虫PDI ( Lm PDI) 在病原体毒力中具有重要作用。此外，抑制LmPDI 进一步阻止了巨噬细胞中的寄生虫感染。在这项研究中，我们利用计算机辅助方法设计了一系列Lm PDI 抑制剂。基于片段的虚拟筛选允许了解抑制剂对Lm PDI 活性位点的作用模式。合成多轮虚拟筛选后获得的化合物，并显着抑制目标Lm PDI 还原酶活性，并显示可减少体外寄生虫在人单核细胞衍生的巨噬细胞中的生长。这种新的化学信息学和合成方法导致了一系列新化合物的鉴定，这些化合物可能被优化为新药物，可能对治疗利什曼病具有更高的特异性和更低的毒性。