Elmaaty Ayman Abo, Darwish Khaled M, Khattab Muhammad, Elhady Sameh S, Salah Mohammed, Hamed Mohammed I A, Al-Karmalawy Ahmed A, Saleh Moustafa M
Department of Medicinal Chemistry, Faculty of Pharmacy, Port Said University, Port Said, Egypt.
Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.
J Biomol Struct Dyn. 2022;40(19):8866-8893. doi: 10.1080/07391102.2021.1918256. Epub 2021 Apr 30.
The global prevalence of COVID-19 disease and the overwhelming increase in death toll urge scientists to discover new effective drugs. Although the drug discovery process is a challenging and time-consuming, fortunately, the plant kingdom was found to have many active therapeutics possessing broad-spectrum antiviral activity including those candidates active against severe acute respiratory syndrome coronaviruses (SARS-CoV). Herein, nine traditional Chinese medicinal plant constituents from different origins (Glycyrrhizin , Lycorine , Puerarin , Daidzein , Daidzin , Salvianolic acid B , Dihydrotanshinone I , Tanshinone I , Tanshinone IIa ) previously reported to exhibit antiviral activity against SARS-CoV were virtually screened (molecular docking) as potential inhibitors of SARS-CoV-2 target proteins. The tested medicinal plant compounds were screened for their activity against two key SARS-CoV-2 target proteins; 3CLpro, and Spike binding-domain proteins. Among the tested medicinal plant compounds, Salvianolic acid B showed promising binding affinities against the two specified SARS-CoV-2 target proteins compared to the reference standards used. Hence molecular dynamics simulations followed by calculating the free-binding energy were carried out for Sal-B providing information on its affinity, stability, and thermodynamic behavior within the two SARS-CoV-2 target proteins as well as key ligand-protein binding aspects. Besides, the quantum mechanical calculations showed that Sal-B can adopt different conformations due to the existence of various rotatable bonds. Therefore, the enhanced antiviral activity of Sal-B among other studied compounds can be also attributed to the structural flexibility of Sal-B. Our study gives an explanation of the structure activity relationship required for targeting SARS-CoV-2 3CLpro and Spike proteins and also facilitates the future design and synthesis of new potential drugs exhibiting better affinity and specificity. Besides, an ADME study was carried out on screened compounds and reference controls revealing their pharmacokinetics properties.Communicated by Ramaswamy H. Sarma.
新型冠状病毒肺炎（COVID-19）疾病的全球流行以及死亡人数的激增促使科学家们去发现新的有效药物。尽管药物研发过程具有挑战性且耗时，但幸运的是，人们发现植物界有许多具有广谱抗病毒活性的活性治疗剂，包括那些对严重急性呼吸综合征冠状病毒（SARS-CoV）有活性的候选药物。在此，对先前报道具有抗SARS-CoV活性的9种来自不同来源的中药植物成分（甘草酸、秋水仙碱、葛根素、大豆苷元、大豆苷、丹酚酸B、二氢丹参酮I、丹参酮I、丹参酮IIA）进行了虚拟筛选（分子对接），以确定它们作为SARS-CoV-2靶蛋白潜在抑制剂的可能性。对所测试的药用植物化合物针对两种关键的SARS-CoV-2靶蛋白（3CL蛋白酶和刺突结合域蛋白）的活性进行了筛选。在所测试的药用植物化合物中，与所使用的参考标准相比，丹酚酸B对两种指定的SARS-CoV-2靶蛋白显示出有前景的结合亲和力。因此，对丹酚酸B进行了分子动力学模拟，随后计算了其自由结合能，以提供有关其在两种SARS-CoV-2靶蛋白中的亲和力、稳定性和热力学行为以及关键配体-蛋白结合方面的信息。此外，量子力学计算表明，由于存在各种可旋转键，丹酚酸B可以采用不同的构象。因此，丹酚酸B在其他研究化合物中增强的抗病毒活性也可归因于其结构灵活性。我们的研究解释了靶向SARS-CoV-2 3CL蛋白酶和刺突蛋白所需的构效关系，也有助于未来设计和合成具有更好亲和力和特异性的新潜在药物。此外，对筛选出的化合物和参考对照进行了药物代谢动力学（ADME）研究，揭示了它们的药代动力学性质。由拉马斯瓦米·H·萨尔马通讯。
