School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen University, Shenzhen 518107, China.
Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200031, China.
Int J Mol Sci. 2024 Apr 26;25(9):4751. doi: 10.3390/ijms25094751.
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 tyrosyl-tRNA synthetase (TyrRS) 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 TyrRS, while showing limited inhibition of human TyrRS. Furthermore, bio-layer interferometry (BLI) confirmed the high affinity of okanin for TyrRS. Molecular dynamics (MD) simulations highlighted the stable conformation of okanin within TyrRS 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 in the blood stage and had little cytotoxicity. Thus, okanin is a promising lead compound for the treatment of malaria caused by .
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，迫切需要新的抗疟药物。氨酰-tRNA 合成酶（aaRSs）是药物开发的有前途的靶点。在这项研究中，我们通过比较人类和疟原虫 TyrRS 的氨基酸序列和三维结构，特别关注氨酰化位点关键氨基酸的差异，确定了酪氨酸-tRNA 合成酶（TyrRS）是抗疟药物开发的潜在靶点。使用高通量热转移测定（TSA）筛选了 2141 种生物活性化合物。Okanin 是一种已知的脂多糖诱导 TLR4 表达抑制剂，对 TyrRS 表现出强烈的抑制活性，同时对人 TyrRS 的抑制作用有限。此外，生物层干涉（BLI）证实了 okanin 与 TyrRS 的高亲和力。分子动力学（MD）模拟突出了 okanin 在 TyrRS 内的稳定构象及其与酶的持续结合。分子对接分析表明，okanin 结合酶的酪氨酸和部分 ATP 结合位点，阻止底物结合。此外，该化合物抑制了血液期的产生，且细胞毒性较小。因此，okanin 是治疗疟原虫引起的疟疾的有前途的先导化合物。
