基于虚拟筛选的 SARS-CoV2 酶抑制剂药物研发,针对病毒附着、复制、翻译后修饰和宿主免疫逃逸感染机制。
Virtual screening-driven drug discovery of SARS-CoV2 enzyme inhibitors targeting viral attachment, replication, post-translational modification and host immunity evasion infection mechanisms.
机构信息
Laboratory for Organic Reactivity, Discovery and Synthesis (LORDS), Research Center for the Natural and Applied Sciences, University of Santo Tomas, Manila, Philippines.
The Graduate School, University of Santo Tomas, Manila, Philippines.
出版信息
J Biomol Struct Dyn. 2021 Aug;39(12):4316-4333. doi: 10.1080/07391102.2020.1776639. Epub 2020 Jun 16.
The novel coronavirus SARS-CoV2, the causative agent of the pandemic disease COVID-19, emerged in December 2019 forcing lockdown of communities in many countries. The absence of specific drugs and vaccines, the rapid transmission of the virus, and the increasing number of deaths worldwide necessitated the discovery of new substances for anti-COVID-19 drug development. With the aid of bioinformatics and computational modelling, ninety seven antiviral secondary metabolites from fungi were docked onto five SARS-CoV2 enzymes involved in viral attachment, replication, post-translational modification, and host immunity evasion infection mechanisms followed by molecular dynamics simulation and ADMET prediction (absorption, distribution, metabolism, excretion and toxicity) of the hit compounds. Thus, three fumiquinazoline alkaloids scedapin C (), quinadoline B () and norquinadoline A (), the polyketide isochaetochromin D1 (), and the terpenoid 11a-dehydroxyisoterreulactone A () exhibited high binding affinities on the target proteins, papain-like protease (PLpro), chymotrypsin-like protease (3CLpro), RNA-directed RNA polymerase (RdRp), non-structural protein 15 (nsp15), and the spike binding domain to GRP78. Molecular dynamics simulation was performed to optimize the interaction and investigate the stability of the top-scoring ligands in complex with the five target proteins. All tested complexes were found to have dynamic stability. Of the five top-scoring metabolites, quinadoline B () was predicted to confer favorable ADMET values, high gastrointestinal absorptive probability and poor blood-brain barrier crossing capacities.Communicated by Ramaswamy H. Sarma.
新型冠状病毒 SARS-CoV2 是导致 COVID-19 大流行的病原体,于 2019 年 12 月出现,迫使许多国家的社区实施封锁。由于缺乏特定的药物和疫苗,病毒传播迅速,全球死亡人数不断增加,因此需要发现新的物质来开发抗 COVID-19 的药物。借助生物信息学和计算建模,对 97 种来自真菌的抗病毒次生代谢产物进行了对接,这些代谢产物与病毒附着、复制、翻译后修饰以及宿主免疫逃逸感染机制相关的 5 种 SARS-CoV2 酶结合,随后对命中化合物进行了分子动力学模拟和 ADMET 预测(吸收、分布、代谢、排泄和毒性)。因此,三种呋喹啉生物碱(scedapin C()、quinadoline B()和 norquinadoline A())、聚酮 isochaetochromin D1()和萜类化合物 11a-脱氢异 Terreulactone A()对靶蛋白木瓜蛋白酶样蛋白酶(PLpro)、糜蛋白酶样蛋白酶(3CLpro)、RNA 依赖性 RNA 聚合酶(RdRp)、非结构蛋白 15(nsp15)和 Spike 结合域与 GRP78 具有高结合亲和力。进行了分子动力学模拟以优化相互作用并研究与五个靶蛋白结合的评分最高配体的稳定性。所有测试的复合物都被发现具有动态稳定性。在五种评分最高的代谢产物中,quinadoline B()被预测具有有利的 ADMET 值、高胃肠道吸收概率和较差的血脑屏障穿透能力。由 Ramaswamy H. Sarma 传达。
相似文献
引用本文的文献
Tetrahedron Chem. 2024-3
Adv Pharmacol Pharm Sci. 2023-6-15
本文引用的文献
J Biomol Struct Dyn. 2021-7
J Biomol Struct Dyn. 2021-7
J Biomol Struct Dyn. 2021-7