Identification of potential inhibitors against SARS-CoV-2 by targeting proteins responsible for envelope formation and virion assembly using docking based virtual screening, and pharmacokinetics approaches
Identification of potential inhibitors against SARS-CoV-2 by targeting proteins responsible for envelope formation and virion assembly using docking based virtual screening, and pharmacokinetics approaches
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DOI：
10.1016/j.meegid.2020.104451
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发表时间：
2020-10-01
影响因子：
3.2
通讯作者：
Kumar, Diwakar
中科院分区：
文献类型：
--
作者：
Bhowmik, Deep;Nandi, Rajat;Kumar, Diwakar
世卫组织已宣布新冠肺炎疫情为国际关注的突发公共卫生事件。不断增长的新病例要求紧急使用特定的抗新冠肺炎药物。三种结构蛋白(膜蛋白、囊膜蛋白和核衣壳蛋白)在感染性病毒粒子的组装和形成中起着重要作用。因此，本研究旨在从548种针对SARS-CoV-2结构蛋白的独特抗病毒化合物(天然和合成抗病毒化合物)中确定潜在的候选药物。高端分子对接分析表征了所选药物-配体与SARS-CoV-2结构蛋白的结合亲和力，而高层模拟研究分析了药物-蛋白质相互作用的稳定性。本研究确定生物类黄酮芦丁和抗生素强力环素是SARS-CoV-2包膜蛋白最有效的抑制物。咖啡酸和阿魏酸对SARS-CoV-2膜蛋白有抑制作用，而抗病毒药物西美普韦和格拉佐韦与核衣壳蛋白有较高的结合亲和力。所有这些化合物不仅表现出良好的药代动力学性质、吸收、代谢、最小毒性和生物利用度，而且在分子动力学模拟过程中仍稳定在蛋白质的活性部位。因此，已鉴定的先导化合物可能通过抑制SARS-CoV-2的包膜形成、病毒粒子组装和病毒致病作用而成为开发有效药物的潜在分子。
WHO has declared the outbreak of COVID-19 as a public health emergency of international concern. The evergrowing new cases have called for an urgent emergency for specific anti-COVID-19 drugs. Three structural proteins (Membrane, Envelope and Nucleocapsid protein) play an essential role in the assembly and formation of the infectious virion particles. Thus, the present study was designed to identify potential drug candidates from the unique collection of 548 anti-viral compounds (natural and synthetic anti-viral), which target SARS-CoV-2 structural proteins. High-end molecular docking analysis was performed to characterize the binding affinity of the selected drugs-the ligand, with the SARS-CoV-2 structural proteins, while high-level Simulation studies analyzed the stability of drug-protein interactions. The present study identified rutin, a bioflavonoid and the antibiotic, doxycycline, as the most potent inhibitor of SARS-CoV-2 envelope protein. Caffeic acid and ferulic acid were found to inhibit SARS-CoV-2 membrane protein while the anti-viral agent's simeprevir and grazoprevir showed a high binding affinity for nucleocapsid protein. All these compounds not only showed excellent pharmacokinetic properties, absorption, metabolism, minimal toxicity and bioavailability but were also remain stabilized at the active site of proteins during the MD simulation. Thus, the identified lead compounds may act as potential molecules for the development of effective drugs against SARS-CoV-2 by inhibiting the envelope formation, virion assembly and viral pathogenesis.