Guevara-Pulido James, Jiménez Ronald A, Morantes Sandra J, Jaramillo Deissy N, Acosta-Guzmán Paola
INQA Facultad de Ciencias Universidad El Bosque Bogotá Colombia.
ChemistrySelect. 2022 Apr 21;7(15):e202200125. doi: 10.1002/slct.202200125. Epub 2022 Apr 19.
A series of chloroquine analogs were designed to search for a less toxic chloroquine derivative as a potential SARS-CoV-2 Mpro inhibitor. Herein, an ANN-based QSAR model was built to predict the IC values of each analog using the experimental values of other 4-aminoquinolines as the training set. Subsequently, molecular docking was used to evaluate each analog's binding affinity to Mpro. The analog that showed the greatest affinity and lowest IC values was synthesized and characterized for its posterior incorporation into a polycaprolactone-based nanoparticulate system. After characterizing the loaded nanoparticles, an drug release assay was carried out, and the cytotoxicity of the analog and loaded nanoparticles was evaluated using murine fibroblast (L929) and human lung adenocarcinoma (A549) cell lines. Results show that the synthesized analog is much less toxic than chloroquine and that the nanoparticulate system allowed for the prolonged release of the analog without evidence of adverse effects on the cell lines used; therefore, suggesting that the analog could be a potential therapeutic option for COVID-19.
设计了一系列氯喹类似物，以寻找一种毒性较低的氯喹衍生物作为潜在的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）主蛋白酶（Mpro）抑制剂。在此，构建了一个基于人工神经网络（ANN）的定量构效关系（QSAR）模型，以使用其他4-氨基喹啉的实验值作为训练集来预测每个类似物的半数抑制浓度（IC）值。随后，使用分子对接来评估每个类似物与Mpro的结合亲和力。合成了表现出最大亲和力和最低IC值的类似物，并对其进行表征，以便随后将其纳入基于聚己内酯的纳米颗粒系统。在对负载的纳米颗粒进行表征后，进行了药物释放试验，并使用小鼠成纤维细胞（L929）和人肺腺癌（A549）细胞系评估了该类似物和负载纳米颗粒的细胞毒性。结果表明，合成的类似物的毒性远低于氯喹，并且纳米颗粒系统允许该类似物延长释放，而没有对所用细胞系产生不利影响的证据；因此，表明该类似物可能是治疗2019冠状病毒病（COVID-19）的一种潜在治疗选择。
