疟原虫是一种单细胞的细胞内原生动物寄生虫，引起人类疟疾，这是一种致命的媒介传播的传染病。疟疾病理学的一个关键阶段是寄生虫蛋白质，包括分子伴侣和共伴侣等寄生虫外源蛋白质的入侵人类红细胞，导致剧烈的重塑。寄生虫在人体宿主内的生存是由疟原虫热休克蛋白70（PfHsp70）和J域蛋白（PfJDP）介导的，它们作为伴侣和共伴侣合作。已经证明了两个复合物对疟疾的生存和病理具有重要作用：PfHsp70-x-PFE0055c（外源）和PfHsp70-2-PfSec63（内质网）。我们对药物再利用库-大流行响应盒(Pandemic Response Box)进行了虚拟筛选，以识别能够特异性破坏这些伴侣复合物的小分子。确定了五个排名靠前的化合物，相比人体系统具有优先结合亲和力的疟疾伴侣系统：三个PfHsp70-PfJDP结合剂，MBX 1641、zoliflodacin和itraconazole；两个J域结合剂，ezetimibe和苯-二氮杂-酮。通过重复的分子对接和分子动力学模拟验证了这些化合物，结果证实除MBX 1461外，所有化合物均优先结合到疟疾伴侣系统。对PfHsp70-PfJDP结合剂的详细接触分析发现了两种不同类型的调节剂，即潜在抑制复合物形成的化合物（MBX 1461）和潜在稳定复合物的化合物（zoliflodacin和itraconazole）。这些数据表明，zoliflodacin和itraconazole是疟疾系统的潜在新型调节剂。对J域结合剂（ezetimibe和苯-二氮杂-酮）的详细接触分析表明，它们与疟疾J域相比人体系统不仅具有更高的亲和力，而且姿势更佳。这些数据表明，ezetimibe和苯-二氮杂-酮是疟疾伴侣系统的潜在特异性抑制剂。伊曲康唑和依泽替米布均为FDA批准的药物，具有抗疟活性，并最近被重新用于癌症治疗。这是首次发现此类药物般化合物作为PfHsp70-PfJDP复合物的潜在调节剂，并且它们代表了新的候选药物，可进行验证和开发成为抗疟药物。 版权 © 2023 Singh，Almaazmi，Dutta，Keyzers和Blatch。

Plasmodium falciparum is a unicellular, intracellular protozoan parasite, and the causative agent of malaria in humans, a deadly vector borne infectious disease. A key phase of malaria pathology, is the invasion of human erythrocytes, resulting in drastic remodeling by exported parasite proteins, including molecular chaperones and co-chaperones. The survival of the parasite within the human host is mediated by P. falciparum heat shock protein 70s (PfHsp70s) and J domain proteins (PfJDPs), functioning as chaperones-co-chaperones partnerships. Two complexes have been shown to be important for survival and pathology of the malaria parasite: PfHsp70-x-PFE0055c (exported); and PfHsp70-2-PfSec63 (endoplasmic reticulum). Virtual screening was conducted on the drug repurposing library, the Pandemic Response Box, to identify small-molecules that could specifically disrupt these chaperone complexes. Five top ranked compounds possessing preferential binding affinity for the malarial chaperone system compared to the human system, were identified; three top PfHsp70-PfJDP binders, MBX 1641, zoliflodacin and itraconazole; and two top J domain binders, ezetimibe and a benzo-diazepinone. These compounds were validated by repeat molecular dockings and molecular dynamics simulation, resulting in all the compounds, except for MBX 1461, being confirmed to bind preferentially to the malarial chaperone system. A detailed contact analysis of the PfHsp70-PfJDP binders identified two different types of modulators, those that potentially inhibit complex formation (MBX 1461), and those that potentially stabilize the complex (zoliflodacin and itraconazole). These data suggested that zoliflodacin and itraconazole are potential novel modulators specific to the malarial system. A detailed contact analysis of the J domain binders (ezetimibe and the benzo-diazepinone), revealed that they bound with not only greater affinity but also a better pose to the malarial J domain compared to that of the human system. These data suggested that ezetimibe and the benzo-diazepinone are potential specific inhibitors of the malarial chaperone system. Both itraconazole and ezetimibe are FDA-approved drugs, possess anti-malarial activity and have recently been repurposed for the treatment of cancer. This is the first time that such drug-like compounds have been identified as potential modulators of PfHsp70-PfJDP complexes, and they represent novel candidates for validation and development into anti-malarial drugs.Copyright © 2023 Singh, Almaazmi, Dutta, Keyzers and Blatch.