Malaria remains the leading cause of deaths globally, despite significant advancement towards understanding its epidemiology and availability of multiple therapeutic interventions. Poor efficacy of the approved vaccine, and the rapid emergence of antimalarial drug resistance, warrants an urgent need to expedite the process of development of new lead molecules targeting malaria. Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes crucial for ribosomal protein synthesis and are valid antimalarial targets. This study explores the prospects of (re-)positioning the repertoire of approved drugs and natural products as potential malarial aaRS inhibitors. Molecular docking of these two sets of small-molecules to lysyl-, prolyl-, and tyrosyl- synthetases from Plasmodium followed by a comparison of the top-ranking docked compounds against human homologs facilitated identification of promising molecular scaffolds. Raltitrexed and Cefprozil, an anticancer drug and an antibiotic, respectively, showed stronger binding to Plasmodium aaRSs compared to human homologs with > 4 kcal/mol difference in the docking scores. Similarly, a difference of ~ 3 kcal/mol in Glide scores was observed for docked Calcipotriol, a drug used for psoriasis treatment, against the two lysyl-tRNA synthetases. Natural products such as Dihydroxanthohumol and Betmidin, having aromatic rings as a substructure, showed preferential docking to the purine binding pocket in Plasmodium tyrosyl-tRNA synthetase as evident from the calculated change in binding free energies. We present detailed analyses of the calculated intermolecular interaction for all top-scoring docked poses. Overall, this study provides a compelling foundation to design and develop specific antimalarials.

尽管在了解其流行病学和多种治疗干预措施的可用性方面取得了重大进展，但疟疾仍然是全球死亡的主要原因。批准的疫苗效力不佳，且抗疟药物耐药性的迅速出现，迫切需要加快开发针对疟疾的新先导分子的进程。氨酰 tRNA 合成酶 (aaRS) 是对核糖体蛋白合成至关重要的必需酶，并且是有效的抗疟靶点。本研究探讨了（重新）定位已批准药物和天然产物作为潜在疟疾 aaRS 抑制剂的前景。这两组小分子与来自疟原虫的赖氨酰-、脯氨酰-和酪氨酰-合成酶的分子对接随后将排名靠前的对接化合物与人类同系物进行比较，有助于识别有前途的分子支架。与人类同源物相比，雷替曲塞和头孢丙烯（一种抗癌药物和抗生素）分别显示出与疟原虫aaRS 的更强结合，对接评分差异 > 4 kcal/mol。类似地，观察到停靠的卡泊三醇（一种用于治疗银屑病的药物）对两种赖氨酰-tRNA 合成酶的 Glide 评分差异约为 3 kcal/mol。天然产物，如二氢黄腐酚和 Betmidin，以芳香环作为亚结构，显示优先与疟原虫中的嘌呤结合口袋对接从结合自由能的计算变化可以看出酪氨酰-tRNA 合成酶。我们对所有得分最高的停靠姿势计算出的分子间相互作用进行了详细分析。总的来说，这项研究为设计和开发特定的抗疟药提供了令人信服的基础。