The ongoing COVID-19 pandemic demands a novel approach to combat and identify potential therapeutic targets. The SARS-CoV-2 infection causes a hyperimmune response followed by a spectrum of diseases. Limonoids are a class of triterpenoids known to prevent the release of IL-6, IL-15, IL-1α, IL-1β via TNF and are also known to modulate PI3K/Akt/GSK-3β, JNK1/2, MAPKp38, ERK1/2, and PI3K/Akt/mTOR signaling pathways and could help to avoid viral infection, persistence, and pathogenesis. The present study employs a computational approach of virtual screening and molecular dynamic (MD) simulations of such compounds against RNA-dependent RNA polymerase (RdRp), Main protease (Mpro), and Papain-like protease (PLpro) of SARS-CoV-2. MD simulation, Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA), and Essential dynamics revealed that the macromolecule-ligand complexes are stable with very low free energy of binding. Such compounds that could modulate both host responses and inhibit viral machinery could be beneficial in effectively controlling the global pandemic.

持续的 COVID-19 大流行需要一种新的方法来对抗和识别潜在的治疗目标。SARS-CoV-2 感染会引起超免疫反应，然后引发一系列疾病。柠檬苦素是一类三萜类化合物，已知可通过 TNF 阻止 IL-6、IL-15、IL-1α、IL-1β 的释放，并且还已知可调节 PI3K/Akt/GSK-3β、JNK1/2、MAPKp38、ERK1 /2 和 PI3K/Akt/mTOR 信号通路，有助于避免病毒感染、持续存在和发病机制。本研究采用虚拟筛选和分子动力学 (MD) 模拟此类化合物对 SARS-CoV-2 的 RNA 依赖性 RNA 聚合酶 (RdRp)、主要蛋白酶 (Mpro) 和木瓜蛋白酶样蛋白酶 (PLpro) 的计算方法. MD 模拟，分子力学泊松-玻尔兹曼表面积 (MM/PBSA)，基本动力学表明，大分子-配体复合物是稳定的，具有非常低的结合自由能。这种既能调节宿主反应又能抑制病毒机制的化合物可能有助于有效控制全球大流行。