PDF(Pubmed)
Abstract：
Malaria is a severe disease that presents a significant threat to human health. As resistance to current drugs continues to increase, there is an urgent need for new antimalarial medications. Aminoacyl-tRNA synthetases (aaRSs) represent promising targets for drug development. In this study, we identified Plasmodium falciparum tyrosyl-tRNA synthetase (PfTyrRS) as a potential target for antimalarial drug development through a comparative analysis of the amino acid sequences and three-dimensional structures of human and plasmodium TyrRS, with particular emphasis on differences in key amino acids at the aminoacylation site. A total of 2141 bioactive compounds were screened using a high-throughput thermal shift assay (TSA). Okanin, known as an inhibitor of LPS-induced TLR4 expression, exhibited potent inhibitory activity against PfTyrRS, while showing limited inhibition of human TyrRS. Furthermore, bio-layer interferometry (BLI) confirmed the high affinity of okanin for PfTyrRS. Molecular dynamics (MD) simulations highlighted the stable conformation of okanin within PfTyrRS and its sustained binding to the enzyme. A molecular docking analysis revealed that okanin binds to both the tyrosine and partial ATP binding sites of the enzyme, preventing substrate binding. In addition, the compound inhibited the production of Plasmodium falciparum in the blood stage and had little cytotoxicity. Thus, okanin is a promising lead compound for the treatment of malaria caused by P. falciparum.
摘要：
疟疾是一种严重的疾病，对人类健康构成重大威胁。随着对现有药物的耐药性不断增加，迫切需要新的抗疟疾药物。氨酰tRNA合成酶（aaRS）代表了药物开发的有希望的靶标。在这项研究中,通过对人类和疟原虫TyrRS的氨基酸序列和三维结构的比较分析，我们确定恶性疟原虫酪氨酰tRNA合成酶（PfTyrRS）是抗疟药开发的潜在靶标，特别强调氨基酰化位点关键氨基酸的差异。使用高通量热转移测定(TSA)筛选总共2141种生物活性化合物。Okanin,被称为LPS诱导的TLR4表达的抑制剂，对PfTyrRS表现出有效的抑制活性，同时显示对人TyrRS的有限抑制。此外，生物层干涉法（BLI）证实了okanin对PfTyrRS的高亲和力。分子动力学（MD）模拟强调了PfTyrRS中奥卡宁的稳定构象及其与酶的持续结合。分子对接分析表明，okanin与酪氨酸和部分ATP结合位点的酶，防止底物结合。此外,该化合物在血液阶段抑制恶性疟原虫的产生，细胞毒性很小。因此，okanin是治疗恶性疟原虫引起的疟疾的有前途的先导化合物。
