Abstract

The pandemic outbreak of the Corona viral infection has become a critical global health issue. Biophysical and structural evidence shows that spike protein possesses a high binding affinity towards host angiotensin-converting enzyme 2 and viral hemagglutinin-acetylesterase (HE) glycoprotein receptor. We selected HE as a target in this study to identify potential inhibitors using a combination of various computational approaches such as molecular docking, ADMET analysis, dynamics simulations and binding free energy calculations. Virtual screening of NPACT compounds identified 3,4,5-Trihydroxy-1,8-bis[(2R,3R)-3,5,7-trihydroxy-3,4-dihydro-2H-chromen-2-yl]benzo[7]annulen-6-one, Silymarin, Withanolide D, Spirosolane and Oridonin as potential HE inhibitors with better binding energy. Furthermore, molecular dynamics simulations for 100 ns time scale revealed that most of the key HE contacts were retained throughout the simulations trajectories. Binding free energy calculations using MM/PBSA approach ranked the top-five potential NPACT compounds which can act as effective HE inhibitors.

Graphic abstract

中文翻译：

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使用分子对接，分子动力学模拟和结合自由能计算确定冠状病毒血凝素酯酶的潜在抑制剂

摘要

电晕病毒感染的大流行爆发已成为全球关键的健康问题。生物物理和结构证据表明，刺突蛋白对宿主血管紧张素转化酶2和病毒血凝素-乙酰酯酶（HE）糖蛋白受体具有很高的结合亲和力。在本研究中，我们选择HE作为目标，以结合各种对接方法（例如分子对接，ADMET分析，动力学模拟和结合自由能计算）来识别潜在抑制剂。虚拟筛选的NPACT化合物确定了3,4,5-三羟基-1,8-双[（2R，3R）-3,5,7-三羟基-3,4-二氢-2 H-chromen-2-yl] benzo [7] annulen-6-one，Silymarin，Withanolide D，spirolsolane和Oridonin作为潜在的HE抑制剂，具有更好的结合能。此外，针对100 ns时间尺度的分子动力学仿真显示，在整个仿真轨迹中，大多数关键的HE接触都得以保留。使用MM / PBSA方法进行的结合自由能计算在排名前五位的潜在NPACT化合物中可作为有效的HE抑制剂。

图形摘要