Ben Khalaf Noureddine, Pham Susie, Romeo Giuseppe, Abdelghany Sara, Intagliata Sebastiano, Sedillo Peter, Salerno Loredana, Gonzales Jessica, Fathallah Dahmani M, Perkins Douglas J, Hurwitz Ivy, Pittalà Valeria
Department of Life Sciences, Health Biotechnology Program, College of Graduates Studies, King Fahd Chair for Health Biotechnology, Arabian Gulf University, Road 2904 Building 293, Manama, 329, Kingdom of Bahrain.
Center for Global Health, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
J Comput Aided Mol Des. 2021 Mar;35(3):297-314. doi: 10.1007/s10822-021-00374-w. Epub 2021 Feb 22.
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，大多数现有的治疗药物都有毒性，超出了该病患者的经济承受能力。蛋白质二硫键异构酶（PDI）是一种伴侣蛋白，在新合成蛋白质的折叠过程中起主要作用，特别是在所有非天然蛋白质的二硫键形成、断裂或重排方面提供协助。在先前的研究中，我们证明了硕大利什曼原虫PDI（LmPDI）在病原体毒力中起着至关重要的作用。此外，抑制LmPDI可进一步阻断寄生虫在巨噬细胞中的感染。在本研究中，我们采用计算机辅助方法设计了一系列LmPDI抑制剂。基于片段的虚拟筛选有助于了解抑制剂对LmPDI活性位点的作用模式。经过多轮虚拟筛选生成的化合物被合成出来，它们显著抑制了目标LmPDI还原酶活性，并显示出可降低人单核细胞衍生巨噬细胞中寄生虫的体外生长。这种新颖的化学信息学和合成方法导致鉴定出了一系列新的化合物，这些化合物可能被优化成新型药物，有望在治疗利什曼病时更具特异性且毒性更低。
