Soto-Sánchez Jacqueline, Pérez-Mora Salvador, Ospina-Villa Juan David, Zavala-Ocampo Lizeth Mariel
Sección de Estudios de Posgrado e Investigación, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Ciudad de México, México.
Instituto Colombiano de Medicina Tropical, Universidad CES, Sabaneta, Antioquia, Colombia.
Curr Comput Aided Drug Des. 2024;20(2):155-169. doi: 10.2174/1573409919666230417135204.
Esters of quinoxaline-7-carboxylate 1,4-di-N-oxide (7-carboxylate QdNOs) derivatives are compounds that inhibit the growth of Entamoeba histolytica, the causative agent of amebiasis. Although these compounds cause changes in the redistribution of glycogen deposits within the parasite, it is unknown whether these compounds interact with enzymes of the glycolytic pathway.
The aim of this study was to test the binding affinity of these compounds to pyrophosphate- dependent phosphofructokinase (PPi-PFK), triosephosphate isomerase (TIM), and pyruvate phosphate dikinase (PPDK) from E. histolytica as a possible mechanism of action.
The molecular docking study of the 7-carboxylate QdNOs derivatives and the proteins was performed using AutoDock/Vina software. Molecular dynamics simulation was performed for 100 ns.
Among all the selected compounds, T-072 exhibited the best binding affinity to EhPPi- PFK and EhTIM proteins, while T-006 interacted best with EhPPDK. ADMET analysis revealed that T-072 was non-toxic, while T-006 could become harmful to the host. In addition, molecular dynamics showed that T-072 has stable interaction with EhPPi-PFK and EhTIM.
Including all aspects, these data indicated that these compounds might inhibit the activity of key enzymes in energy metabolism leading to parasite death. Furthermore, these compounds may be a good starting point for the future development of new potent antiamebic agents.
喹喔啉 - 7 - 羧酸1,4 - 二 - N - 氧化物（7 - 羧酸QdNOs）衍生物是抑制溶组织内阿米巴生长的化合物，溶组织内阿米巴是阿米巴病的病原体。尽管这些化合物会导致寄生虫体内糖原沉积的重新分布发生变化，但尚不清楚这些化合物是否与糖酵解途径的酶相互作用。
本研究的目的是测试这些化合物与溶组织内阿米巴的焦磷酸依赖性磷酸果糖激酶（PPi - PFK）、磷酸丙糖异构酶（TIM）和丙酮酸磷酸双激酶（PPDK）的结合亲和力，作为一种可能的作用机制。
使用AutoDock/Vina软件对7 - 羧酸QdNOs衍生物和蛋白质进行分子对接研究。进行了100纳秒的分子动力学模拟。
在所有选定的化合物中，T - 072对EhPPi - PFK和EhTIM蛋白表现出最佳的结合亲和力，而T - 006与EhPPDK的相互作用最佳。ADMET分析表明，T - 072无毒，而T - 006可能对宿主有害。此外，分子动力学表明T - 072与EhPPi - PFK和EhTIM具有稳定的相互作用。
综合各方面来看，这些数据表明这些化合物可能抑制能量代谢中的关键酶活性，导致寄生虫死亡。此外，这些化合物可能是未来开发新型强效抗阿米巴药物的良好起点。
