PDF(Pubmed)
Abstract：
The Covid-19 pandemic outbreak has accelerated tremendous efforts to discover a therapeutic strategy that targets severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to control viral infection. Various viral proteins have been identified as potential drug targets, however, to date, no specific therapeutic cure is available against the SARS-CoV-2. To address this issue, the present work reports a systematic cheminformatic approach to identify the potent andrographolide derivatives that can target methyltransferases of SARS-CoV-2, i.e. nsp14 and nsp16 which are crucial for the replication of the virus and host immune evasion. A consensus of cheminformatics methodologies including virtual screening, molecular docking, ADMET profiling, molecular dynamics simulations, free-energy landscape analysis, molecular mechanics generalized born surface area (MM-GBSA), and density functional theory (DFT) was utilized. Our study reveals two new andrographolide derivatives (PubChem CID: 2734589 and 138968421) as natural bioactive molecules that can form stable complexes with both proteins via hydrophobic interactions, hydrogen bonds and electrostatic interactions. The toxicity analysis predicts class four toxicity for both compounds with LD50 value in the range of 500-700 mg/kg. MD simulation reveals the stable formation of the complex for both the compounds and their average trajectory values were found to be lower than the control inhibitor and protein alone. MMGBSA analysis corroborates the MD simulation result and showed the lowest energy for the compounds 2734589 and 138968421. The DFT and MEP analysis also predicts the better reactivity and stability of both the hit compounds. Overall, both andrographolide derivatives exhibit good potential as potent inhibitors for both nsp14 and nsp16 proteins, however, in-vitro and in vivo assessment would be required to prove their efficacy and safety in clinical settings. Moreover, the drug discovery strategy aiming at the dual target approach might serve as a useful model for inventing novel drug molecules for various other diseases.
摘要：
新冠肺炎大流行的爆发加速了巨大的努力，以发现一种针对严重急性呼吸道综合症冠状病毒2(SARS-CoV-2)的治疗策略来控制病毒感染。各种病毒蛋白已被确定为潜在的药物靶标，然而,到目前为止,没有针对SARS-CoV-2的特定治疗方法。为了解决这个问题，本工作报告了一种系统的化学信息学方法来鉴定有效的穿心莲内酯衍生物，这些衍生物可以靶向SARS-CoV-2的甲基转移酶，即nsp14和nsp16，这对病毒的复制和宿主免疫逃避至关重要。化学信息学方法的共识，包括虚拟筛选，分子对接,ADMET分析，分子动力学模拟，自由能景观分析，分子力学广义表面积(MM-GBSA)，并利用密度泛函理论(DFT)。我们的研究揭示了两种新的穿心莲内酯衍生物（PubChemCID：2734589和138968421）作为天然生物活性分子，可以通过疏水相互作用与两种蛋白质形成稳定的复合物，氢键和静电相互作用。毒性分析预测LD50值在500-700mg/kg范围内的两种化合物的第四类毒性。MD模拟揭示了两种化合物的复合物的稳定形成,并且发现它们的平均轨迹值低于对照抑制剂和单独的蛋白质。MMGBSA分析证实了MD模拟结果并且显示化合物2734589和138968421的最低能量。DFT和MEP分析还预测了两种命中化合物的更好的反应性和稳定性。总的来说,这两种穿心莲内酯衍生物表现出良好的潜力，作为强效抑制剂的nsp14和nsp16蛋白，然而,需要进行体外和体内评估,以证明其在临床中的有效性和安全性.此外，针对双靶点方法的药物发现策略可能成为发明其他各种疾病的新型药物分子的有用模型。
