基于数据挖掘和网络药理学方法探究新型冠状病毒肺炎验案核心组方的中药特性及分子机制

Exploration of the characteristic and molecular mechanism of Chinese herbal medicines in the core formula for COVID-19’s cases based on data mining and network pharmacology

目的基于数据挖掘和网络药理学方法,探究新型冠状病毒肺炎(COVID-19)验案核心组方的临证价值及分子机制。方法借助"古今医案云平台(V2.2.1)"录入已发表的新型冠状病毒肺炎验案中药处方,进行证型统计、中药四气五味归经分析,挖掘其中的用药规律,初步获得核心组方;再运用"中药系统药理学分析平台(TCMSP)"检索核心组方有效活性成分及作用靶点,运用GeneCards等数据库对疾病靶点进行筛选,使用Cytoscape3.7.2软件构建活性成分-靶点网络和PPI蛋白互作网络;通过DAVID数据库对靶点进行GO功能分析和KEGG通路富集分析后将核心组方进一步精简化,最后使用Autodockvina进行分子对接,初步筛选并进一步验证核心验案中药物与新型冠状病毒肺炎关键靶点结合的核心化学成分集。结果①共得到临床验案38例,共收集处方77首,涉及中药164味;药物四气多属寒、温、平,五味多属苦、辛、甘,主要归属肺、胃、脾经;得到77首处方的核心方药组14个,主要涉及药物包括:厚朴、草豆蔻、甘草、桔梗、柴胡、苦杏仁、黄芩、陈皮、茯苓、连翘、半夏、广藿香。②核心组方的有效活性成分共87个,可通过56个潜在靶标作用于COVID-19。③富集分析得到GO中1 522个生物过程条目和161条KEGG通路(P<0.05),由此精简组方后保留草豆蔻、柴胡、广藿香、连翘、桔梗、黄芩、陈皮为最终核心组方,涉及抗炎、抗氧化、抗纤维化、抑制细胞凋亡、抑制病毒复制等多过程。结论中医治疗新冠肺炎临床验案中的核心药组属于寒、温、平并用,主要作用于肺、胃、脾经;其主要是通过黄酮类活性成分调节IL-6、MAPK1、MAPK8、CASP3、IL-1B、RELA、MAPK14、MAPK3、PTGS2、CCL2、FOS等关键靶点,调控MAPK、NFKB、TNF、IL-17等信号通路来治疗COVID-19。

Objective To explore the clinical value and molecular mechanism of the core formula for novel coronavirus’ s pneumonia(COVID-19) based on data mining and network pharmacology. Methods With the help of the Cloud Platform of Ancient and Modern Medical Records(V2.2.1), the published prescriptions of Chinese herbal medicines for COVID-19 were recorded, the statistics of syndrome patterns and the analysis of four qi and five flavors of traditional Chinese medicine were carried out, the rules of medication were excavated, and thus the core formula was preliminarily obtained. Then the active components and action targets of the core formula were searched by Traditional Chinese Medicine System Pharmacology Analysis Platform(TCMSP). The disease targets were screened by Gene Cards and other databases,and the active component-target network and PPI protein interaction network were constructed by Cytoscape 3. 7. 2 software. After GO function analysis and KEGG pathway enrichment analysis of the target through DAVID database,the core formula was further refined and simplified.Finally,Autodockvina was used for molecular docking,preliminary screening and further verification of the core chemical composition set of Chinese herbal medicines used in core cases bound to the key target of COVID-19. Results(1)A total of 38 clinical cases were obtained,and 77 prescriptions were collected,involving 164 Chinese herbal medicines. The four qi of the herbs are mostly cold,warm and mild,and the five flavors of the herbs are mostly bitter,pungent and sweet,which mainly belong to lung,stomach and spleen channels. Fourteen core formulae had obtained from 77 prescriptions,which include Houpu(Cortex Magnoliae Officinalis),Caodoukou(Semen Alpiniae Katsumadai),Gancao(Radix Glycyrrhizae),Jiegeng(Radix Platycodi),Chaihu(Radix Bupleuri),Kuxingren(Semen Armeniacae Amarum),Huangqin(Radix Scutellariae),Chenpi(Pericarpium Citri Reticula),Fuling(Poria),Lianqiao(Fructus Forsythiae),Banxia(Rhizoma Pinelliae),Guanghuoxiang(Herba Pogostemonis).(2)There are 87 active components in the core formula,which can act on covid-19 through 56 potential targets.(3)A total of 1 522 bioprocess entries and 161 KEGG pathways in GO were obtained by enrichment analysis(P<0.05). As a result,the formula was simplified and the herbs were retained such as Caodoukou(Semen Alpiniae Katsumadai),Chaihu(Radix Bupleuri),Guanghuoxiang(Herba Pogostemonis),Lianqiao(Fructus Forsythiae),Jiegeng(Radix Platycodi),Huangqin(Radix Scutellariae),Chenpi(Pericarpium Citri Reticula) as the final core formula. It involves anti-inflammatory,anti-oxidation,anti-fibrosis,inhibition of apoptosis,inhibition of virus replication and other processes. Conclusion The core formula for the clinical cases of COVID-19 belongs to the combination of cold,warm and mild in nature,mainly acting in lung,stomach and spleen channels. It mainly regulates key targets such as IL-6,MAPK1,MAPK8,CASP3,IL-1 B,RELA,MAPK14,MAPK3,PTGS2,CCL2,FOS and regulates signal pathways such as MAPK,NFk B,TNF,IL-17 to treat COVID-19.