Abstract

COVID-19 is a respiratory disease caused by SARS-CoV-2, an enveloped positive sense RNA virus. The SARS-CoV-2 spike glycoprotein, human angiotensin-converting enzyme 2 (ACE2) and human transmembrane protease serine 2 (TMPRSS2) are essential for the host cell-mediated viral entry. Targeting these proteins represent viable options to stop the first stage of infection and transmission. Hence, 97 alkaloids from African medicinal plants with reported antiviral activity were evaluated for this purpose via in silico studies. These alkaloids were docked for their interactions with SARS-CoV-2 spike glycoprotein, ACE2, and TMPRSS2. Top 20 alkaloids with highest binding affinities were further screened for their interactions with spike glycoprotein of SARS-CoV and MERS-CoV, and with ACE2-SARS-CoV-2 receptor-binding domain complex (ACE2-RBD). The energy profiling, molecular dynamics simulation (MDS), binding free energy base on Molecular Mechanics/Generalized Born Surface Area (MMGBSA), clustering of MDS trajectories, and virtual physicochemical and pharmacokinetic screening of the best docked alkaloids were performed. Results revealed that more than 15 alkaloids interacted better than the reference compounds. 10–Hydroxyusambarensine and Cryptospirolepine were docked in a similar binding pattern to the S1-specificy pocket of TMPRSS2 as camostat (reference inhibitor). The strong binding affinities, stability of the alkaloid-protein complexes and amino acid interactions displayed by cryptospirolepine, 10-hydroxyusambarensine, and cryptoquindoline with important binding hotspots of the proteins suggest these alkaloids have the potential of altering the capacity of SARS-CoV-2 membrane mediated host cell entry. Further in vitro and in vivo evaluation of these “drug-like” alkaloids as potential inhibitors of coronavirus cell entry is proposed.

Communicated by Ramaswamy H. Sarma

摘要

COVID-19 是由 SARS-CoV-2（一种包膜正链 RNA 病毒）引起的呼吸道疾病。SARS-CoV-2 刺突糖蛋白、人血管紧张素转换酶 2 (ACE2) 和人跨膜蛋白酶丝氨酸 2 (TMPRSS2) 对于宿主细胞介导的病毒进入至关重要。针对这些蛋白质是阻止第一阶段感染和传播的可行选择。因此，为此目的，通过计算机研究对来自非洲药用植物的 97 种具有抗病毒活性的生物碱进行了评估。这些生物碱因与 SARS-CoV-2 刺突糖蛋白、ACE2 和 TMPRSS2 的相互作用而被对接。进一步筛选了结合亲和力最高的前 20 种生物碱与 SARS-CoV 和 MERS-CoV 刺突糖蛋白以及 ACE2-SARS-CoV-2 受体结合域复合物 (ACE2-RBD) 的相互作用。进行了能量分析、分子动力学模拟（MDS）、基于分子力学/广义玻恩表面积（MMGBSA）的结合自由能、MDS轨迹聚类以及最佳对接生物碱的虚拟物理化学和药代动力学筛选。结果表明，超过 15 种生物碱的相互作用比参考化合物更好。10-Hydroxyusambarensine 和 Cryptospirolepine 以类似的结合模式与作为卡莫司他（参考抑制剂）的 TMPRSS2 的 S1 特异性口袋对接。Cryptospirolepine、10-羟基usambarensine 和 Cryptoquindoline 表现出的强结合亲和力、生物碱-蛋白质复合物的稳定性以及氨基酸相互作用与蛋白质的重要​​结合热点表明这些生物碱具有改变 SARS-CoV-2 膜能力的潜力介导宿主细胞进入。建议对这些“类药物”生物碱作为冠状病毒细胞进入的潜在抑制剂进行进一步的体外和体内评估。

拉马斯瓦米·萨尔马 (Ramaswamy H. Sarma) 通讯