Sobota Sydni, Devaraja Shiffany, Chung Matthew, Arevalo Justin, Martinez-Aguirre Jonathan, Makeyenko Jastina, Kellen-Yuen Cynthia, Eastman Sam, Derbyshire Emily, Saade Christelle, Dieudonné Thibaud, Paula Stefan
Department of Chemistry, California State University Sacramento, 6000 J Street, Sacramento, CA 95819, USA.
Department of Chemistry, Duke University, 124 Science Drive, Durham, NC 27708, USA.
Bioorg Med Chem. 2025 Nov 1;129:118342. doi: 10.1016/j.bmc.2025.118342. Epub 2025 Aug 7.
Malaria, an infectious disease caused by Plasmodium parasites, continues to pose a serious global health problem. PfATP6, a calcium-transporting transmembrane protein present in Plasmodium falciparum, has been identified as a promising target for new antimalarial drugs, prompting searches for specific and potent inhibitors of this enzyme. Such compounds also have the potential of becoming novel research tools for the elucidation of the enzyme's physiological functions. However, only a few PfATP6 inhibitors are known to date and most of them suffer from limitations due to their high structural complexity, with high costs that restrict their availability. A notable exception is a group of structurally simple phenolic compounds that feature hydroquinone and naphthoquinone scaffolds. In order to assess the potential of this compound class as future antimalarials, we characterized a small library of these molecules in P. falciparum blood stage viability and PfATP6 activity inhibition assays. Several compounds were able to inhibit parasite growth, amongst them di-alkylated hydroquinones, a naphthoquinone disulfide, and hexachlorophene, a disinfectant. Some of the antiplasmodial compounds were also able to inhibit the activity of the purified enzyme, even though the correlation between these two properties was not absolute. The molecular interactions of active compounds with PfATP6 were analyzed by homology modeling, ligand docking, and molecular dynamics simulations, revealing a combination of hydrogen bonding and hydrophobic interactions as the main contributors to binding. The gained information constitutes a first step toward the future design of small-molecule PfATP6 inhibitors with improved properties.
疟疾是一种由疟原虫寄生虫引起的传染病，仍然是一个严重的全球健康问题。PfATP6是一种存在于恶性疟原虫中的钙转运跨膜蛋白，已被确定为新型抗疟药物的一个有前景的靶点，这促使人们寻找该酶的特异性强效抑制剂。这类化合物也有可能成为阐明该酶生理功能的新型研究工具。然而，迄今为止已知的PfATP6抑制剂只有少数几种，而且它们中的大多数由于结构高度复杂而存在局限性，成本高昂限制了其可用性。一个显著的例外是一组具有对苯二酚和萘醌支架结构的简单酚类化合物。为了评估这类化合物作为未来抗疟药物的潜力，我们在恶性疟原虫血液阶段生存力和PfATP6活性抑制试验中对这些分子的一个小文库进行了表征。几种化合物能够抑制寄生虫生长，其中包括二烷基化对苯二酚、一种萘醌二硫化物和一种消毒剂六氯酚。一些抗疟化合物也能够抑制纯化酶的活性，尽管这两种性质之间的相关性并非绝对。通过同源建模、配体对接和分子动力学模拟分析了活性化合物与PfATP6的分子相互作用，揭示了氢键和疏水相互作用的组合是结合的主要贡献因素。所获得的信息是朝着未来设计具有改进性质的小分子PfATP6抑制剂迈出的第一步。
