基于分子对接和分子动力学的N-0385阻断严重急性呼吸综合征冠状病毒2治疗冠状病毒病19的机制
Mechanism of N-0385 blocking SARS-CoV-2 to treat COVID-19 based on molecular docking and molecular dynamics.
作者信息
Cao Jun-Feng, Yang Xingyu, Xiong Li, Wu Mei, Chen Shengyan, Xiong Chenyang, He Peiyong, Zong Yonghua, Zhang Lixin, Fu Hongjiao, Qi Yue, Ying Xiran, Liu Dengxin, Hu Xiaosong, Zhang Xiao
机构信息
Clinical Medicine, Chengdu Medical College, Chengdu, China.
University of Tibetan Medicine, Lhasa, China.
出版信息
Front Microbiol. 2022 Oct 18;13:1013911. doi: 10.3389/fmicb.2022.1013911. eCollection 2022.
PURPOSE
2019 Coronavirus disease (COVID-19) has caused millions of confirmed cases and deaths worldwide. TMPRSS2-mediated hydrolysis and maturation of spike protein is essential for SARS-CoV-2 infection . The latest research found that a TMPRSS2 inhibitor called N-0385 could effectively prevent the infection of the SARS-CoV-2 and its variants. However, it is not clear about the mechanism of N-0385 treatment COVID-19. Therefore, this study used computer simulations to investigate the mechanism of N-0385 treatment COVID-19 by impeding SARS-CoV-2 infection.
METHODS
The GeneCards database was used to search disease gene targets, core targets were analyzed by PPI, GO and KEGG. Molecular docking and molecular dynamics were used to validate and analyze the binding stability of small molecule N-0385 to target proteins. The supercomputer platform was used to simulate and analyze the number of hydrogen bonds, binding free energy, stability of protein targets at the residue level, radius of gyration and solvent accessible surface area.
RESULTS
There were 4,600 COVID-19 gene targets from GeneCards database. PPI, GO and KEGG analysis indicated that signaling pathways of immune response and inflammation played crucial roles in COVID-19. Molecular docking showed that N-0385 could block SARS-CoV-2 infection and treat COVID-19 by acting on ACE2, TMPRSS2 and NLRP3. Molecular dynamics was used to demonstrate that the small molecule N-0385 could form very stable bindings with TMPRSS2 and TLR7.
CONCLUSION
The mechanism of N-0385 treatment COVID-19 was investigated by molecular docking and molecular dynamics simulation. We speculated that N-0385 may not only inhibit SARS-CoV-2 invasion directly by acting on TMPRSS2, ACE2 and DPP4, but also inhibit the immune recognition process and inflammatory response by regulating TLR7, NLRP3 and IL-10 to prevent SARS-CoV-2 invasion. Therefore, these results suggested that N-0385 may act through multiple targets to reduce SARS-CoV-2 infection and damage caused by inflammatory responses.
目的
2019冠状病毒病（COVID-19）已在全球造成数百万确诊病例和死亡。跨膜丝氨酸蛋白酶2（TMPRSS2）介导的刺突蛋白水解和成熟对于严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染至关重要。最新研究发现，一种名为N-0385的TMPRSS2抑制剂可有效预防SARS-CoV-2及其变体的感染。然而，N-0385治疗COVID-19的机制尚不清楚。因此，本研究采用计算机模拟来研究N-0385通过阻止SARS-CoV-2感染治疗COVID-19的机制。
方法
利用基因卡片（GeneCards）数据库搜索疾病基因靶点，通过蛋白质-蛋白质相互作用（PPI）、基因本体（GO）和京都基因与基因组百科全书（KEGG）分析核心靶点。采用分子对接和分子动力学来验证和分析小分子N-0385与靶蛋白的结合稳定性。利用超级计算机平台模拟和分析氢键数量、结合自由能、蛋白质靶点在残基水平的稳定性、回转半径和溶剂可及表面积。
结果
基因卡片数据库中有4600个COVID-19基因靶点。PPI、GO和KEGG分析表明，免疫反应和炎症信号通路在COVID-19中起关键作用。分子对接显示，N-0385可通过作用于血管紧张素转换酶2（ACE2）、TMPRSS2和NOD样受体蛋白3（NLRP3）来阻断SARS-CoV-2感染并治疗COVID-19。分子动力学表明，小分子N-0385可与TMPRSS2和Toll样受体7（TLR7）形成非常稳定的结合。
结论
通过分子对接和分子动力学模拟研究了N-0385治疗COVID-19的机制。我们推测，N-0385可能不仅通过作用于TMPRSS2、ACE2和二肽基肽酶4（DPP4）直接抑制SARS-CoV-2入侵，还通过调节TLR7、NLRP3和白细胞介素10（IL-10）来抑制免疫识别过程和炎症反应，以防止SARS-CoV-2入侵。因此，这些结果表明，N-0385可能通过多个靶点发挥作用，以减少SARS-CoV-2感染和炎症反应造成的损害。
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