Bostancioglu Safiye Merve, Mutlu Ozal
Department of Biology, Faculty of Science, Marmara University, Goztepe, 34722, Istanbul, Türkiye.
Parasitol Res. 2025 Jan 7;124(1):1. doi: 10.1007/s00436-024-08433-5.
Babesia bigemina is an apicomplexan parasite responsible for causing "Texas fever" in bovines. Current treatments for bovine babesiosis are hindered by several limitations, including toxicity, insufficient efficacy in eliminating the parasite, and the potential for resistance development. A promising approach to overcome these challenges is the identification of compounds that specifically target essential metabolic pathways unique to the parasite. One such target is lactate dehydrogenase (LDH), a critical enzyme involved in the regulation of anaerobic glycolysis. Notably, Babesia bigemina LDH (BbigLDH) exhibits a five-amino acid insertion in the active site, a feature that differentiates it from the host's LDH. This structural divergence makes apicomplexan LDH an attractive and potentially selective drug target for therapeutic intervention. In this study, a structure-based drug discovery approach was implemented to find novel inhibitor candidates. Potential candidates were identified using a virtual screening workflow. The compounds with favorable docking scores were filtered using the QM-polarized ligand docking and induced fit docking methods. As a result, 20 novel compounds were identified that bind to the active site of BbigLDH but show low affinity to the host LDHs. Molecular dynamics simulations of the complexes (8.8 µs in total) were performed, and binding free energies were calculated. As a result, protein structures containing compounds C9, C16 and C18 maintained their stability throughout 1 µs simulations with low binding free energies and conserved interactions with known catalytic residues. Therefore, these three compounds deserve further investigation to better understand their mode of action and therapeutic potential for babesiosis. The results of this study elucidate the structural features of the BbigLDH enzyme and provide novel LDH binders that may pave the way for further research into the development of parasite-specific LDH inhibitors.
双芽巴贝斯虫是一种顶复门寄生虫，可导致牛患上“得克萨斯热”。目前用于治疗牛巴贝斯虫病的方法存在若干局限性，包括毒性、消除寄生虫的疗效不足以及产生耐药性的可能性。克服这些挑战的一种有前景的方法是鉴定特异性靶向该寄生虫独特的必需代谢途径的化合物。其中一个这样的靶点是乳酸脱氢酶（LDH），它是参与无氧糖酵解调节的关键酶。值得注意的是，双芽巴贝斯虫乳酸脱氢酶（BbigLDH）在活性位点有一个五氨基酸插入，这一特征使其与宿主的LDH不同。这种结构差异使得顶复门LDH成为治疗干预中一个有吸引力且可能具有选择性的药物靶点。在本研究中，实施了一种基于结构的药物发现方法来寻找新的抑制剂候选物。使用虚拟筛选工作流程鉴定潜在候选物。使用量子力学极化配体对接和诱导契合对接方法对具有良好对接分数的化合物进行筛选。结果，鉴定出20种与BbigLDH活性位点结合但对宿主LDH亲和力较低的新化合物。对复合物进行了分子动力学模拟（总共8.8微秒），并计算了结合自由能。结果，含有化合物C9、C16和C18的蛋白质结构在整个1微秒的模拟过程中保持稳定，结合自由能较低，并且与已知催化残基的相互作用保守。因此，这三种化合物值得进一步研究，以更好地了解它们的作用方式和对巴贝斯虫病的治疗潜力。本研究结果阐明了BbigLDH酶的结构特征，并提供了新的LDH结合物，这可能为进一步研究开发寄生虫特异性LDH抑制剂铺平道路。
