Abstract

In this work we aimed to perform an in silico predictive screening, docking and molecular dynamic study to identify 1,2,3-triazole-phthalimide derivatives as drug candidates against SARS-CoV-2. The in silico prediction of pharmacokinetic and toxicological properties of hundred one 1,2,3-triazole-phtalimide derivatives, obtained from SciFinder® library, were investigated. Compounds that did not show good gastrointestinal absorption, violated the Lipinski's rules, proved to be positive for the AMES test, and showed to be hepatotoxic or immunotoxic in our ADMET analysis, were filtered out of our study. The hit compounds were further subjected to molecular docking on SARS-CoV-2 target proteins. The ADMET analysis revealed that 43 derivatives violated the Lipinski’s rules and 51 other compounds showed to be positive for the toxicity test. Seven 1,2,3-triazole-phthalimide derivatives (A7, A8, B05, E35, E38, E39, and E40) were selected for molecular docking and MFCC—ab initio analysis. The results of molecular docking pointed the derivative E40 as a promising compound interacting with multiple target proteins of SARS-CoV-2. The complex E40-M^pro was found to have minimum binding energy of −10.26 kcal/mol and a general energy balance, calculated by the quantum mechanical analysis, of −8.63 eV. MD simulation and MMGBSA calculations confirmed that the derivatives E38 and E40 have high binding energies of −63.47 ± 3 and −63.31 ± 7 kcal/mol against SARS-CoV-2 main protease. In addition, the derivative E40 exhibited excellent interaction values and inhibitory potential against SAR-Cov-2 main protease and viral nucleocapsid proteins, suggesting this derivative as a potent antiviral for the treatment and/or prophylaxis of COVID-19.

Communicated by Ramaswamy H. Sarma

 抽象的

在这项工作中，我们旨在进行计算机预测筛选、对接和分子动力学研究，以确定 1,2,3-三唑-邻苯二甲酰亚胺衍生物作为抗 SARS-CoV-2 的候选药物。研究了从 SciFinder® 库中获得的 100 种 1,2,3-三唑-邻苯二甲酰亚胺衍生物的药代动力学和毒理学特性的计算机预测。胃肠道吸收不良、违反 Lipinski 规则、AMES 测试呈阳性以及在我们的 ADMET 分析中显示出肝毒性或免疫毒性的化合物被从我们的研究中过滤掉。命中的化合物进一步与 SARS-CoV-2 靶蛋白进行分子对接。 ADMET 分析显示，43 种衍生物违反了 Lipinski 规则，另外 51 种化合物的毒性测试呈阳性。选择七种 1,2,3-三唑-邻苯二甲酰亚胺衍生物（ A7 、 A8 、 B05 、 E35 、 E38 、 E39和E40 ）进行分子对接和 MFCC从头计算分析。分子对接结果表明，衍生物E40是一种有前景的化合物，可以与 SARS-CoV-2 的多个靶蛋白相互作用。复合物E40 - M ^pro的最小结合能为-10.26 kcal/mol，通过量子力学分析计算出的一般能量平衡为-8.63 eV。 MD模拟和MMGBSA计算证实，衍生物E38和E40对SARS-CoV-2主要蛋白酶具有-63.47 ± 3和-63.31 ± 7 kcal/mol的高结合能。 此外，衍生物E40对SAR-Cov-2主要蛋白酶和病毒核衣壳蛋白表现出优异的相互作用值和抑制潜力，表明该衍生物可作为治疗和/或预防COVID-19的有效抗病毒药物。

拉马斯瓦米·萨尔马 (Ramaswamy H. Sarma) 通讯