基于网络药理学研究思路探索热毒宁注射液治疗URTI的作用机制
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摘要
热毒宁注射液由金银花(Lonicera Japonica)、栀子(Gardenia Jasminioides)、青蒿(Artemisia Annua)三味中药制备而成,具有清热、疏风、解毒之功效,主要用于上呼吸道感染(URTI)的治疗。前期药理研究表明其有多种药理作用,可降低多种呼吸道病毒载量、抑制PGE2、IL-1、ET等多种炎症因子分泌；临床研究显示能明显缓解上呼吸道感染(URTI)患者的高热、咳嗽等症状。但其治疗URTI的分子机制目前尚不清楚,根据已报道的部分成分作用机制研究和相应的中医理论,疾病是机体整体功能的失衡,中药作用在于调整失衡状态恢复到平衡状态(健康),故推测其作用机制可能是所含活性成分对整个疾病网络的整体调控。
本文采用主成分分析、分子对接、网络分析以及体外细胞实验等方法对分析了热毒宁注射液中化学成分的空间结构分布、进行了化学分子和与URTI发病机制相关靶蛋白的分子对接,计算了靶蛋白与化学分子的相互作用网络特征,进而预测出热毒宁注射液治疗URTI的分子作用机制、主要活性成分群和可能的适应症,并从细胞水平和蛋白表达水平对所预测的热毒宁注射液抗炎、抗流感病毒分子机制进行了初步的试验验证。通过尝试运用网络药理学研究思路对热毒宁注射液治疗URTI的作用机制探索,明确了热毒宁注射液多组分、多靶点、多途径的作用机制,为其更好的临床应用提供理论支撑,也是对网络药理学在中药作用机制研究方面的有益探索。
1.热毒宁注射液化学分子和URTI靶蛋白数据库构建
根据URTI发病机制分析和前期热毒宁注射液化学成分的系统研究,通过TTD、 DrugBank、PDB、Bestelin、UNPD等数据库检索到含有原配体的51个靶蛋白晶体结构和58个化合物的78个化学分子的三维结构。利用DiscoveryStudio2.5中General Purpose对化学分子的分子描述符,并通过与已上市的用于治疗URTI的38个药物进行化学结构相似分析,发现热毒宁注射液中绝大部分化学成分具有较好的类药性和较好的生物利用度,其与治疗URTI的药物在化学结构上有较大的相似性,提示所选择的化合物包含了热毒宁注射液治疗URTI的活性化合物,同时也说明了热毒宁注射液中含有与治疗URTI相关的活性化合物。
2.热毒宁注射液分子对接与网络分析
应用Autodock计算化学分子与靶蛋白,再以原配体为阂值,取对接分值较高的化合物(score>=5)导入Cytoscape2.8.1构建生物网络,并通过网络特征分析(包括网络度、介数、网络密度等)发现：a)有25个化学分子与3个以上的靶蛋白存在较强相互作用,其中7个分子对网络的影响比较大(介数比较高),且与7个以上靶蛋白存在作用,而这些靶蛋白分布于病毒复制、炎症介质分泌以及胞内信号转导等环节,推测这些分子在热毒宁注射液治疗URTI中有极重要的地位；b)有4个小分子在分子-分子网络中处于桥连点的位置,有助于保证网络中不同模块间的信息流通,推测其在热毒宁注射液中与其它分子可能存在协同作用：c)靶点分析表明热毒宁注射液缓解URTI症状的分子机制可能是抑制病毒(流感病毒、鼻病毒以及呼吸道合胞病毒等)胞内复制、调控MAPKs、PI3K-Akt、JAK-STAT、 NF-kB信号通路、降低炎症因子(IL-1、 IL-6、NO、PGE2等)分泌,最终促进炎性机体恢复到平衡状态。
3.热毒宁注射液分子抗炎、抗病毒活性验证
通过测定热毒宁注射液中28个化合物对LPS刺激RAW264.7释放PGE2、NO的抑制作用,发现16个活性化合物(抑制率>=50%)；结合预测结果可知,其中9个可能是通过调控MAPKs、JAK、NF-kB信号通路影响COX、 mPGES-1、iNOS的表达或/和直接抑制PLA2、COX、mPGES-1、iNOS酶的活性来降低PGE2、NO含量,而进一步对COX-2、 mPGES-1、iNOS蛋白表达的分析发现在预测可调控MAPKs、JAK信号通路的(RDN3、 RDN4、 RDN5、RDN11、RDN18、RDN22、RDN27)7个化合物中,5个化合物(RDN3、 RDN5、RDN18、RDN22、RDN27)被证实其抑制PGE2、 NO分泌的作用与降低的COX-2、 mPGES-1、iNOS蛋白表达有关。
通过对热毒宁注射液中28个化合物的抗流感病毒实验发现,与HA、NA、SAH、IMP dehydrogenase等多个病毒复制环节蛋白存在相互作用的RDN11对A型流感病毒有较强的抑制活性(EC50=28.44μM, SI=24.66),而与HA、IMP dehydrogenase有相互作用但对整个生物网络影响较小的RDN14对A型流感病毒有较弱的抑制活性(EC50=91.284μM,SI=5.48)。
两次验证结果表明,基于网络药理学研究思路下的热毒宁注射液分子对接与网络分析预测中药分子与靶蛋白的相互作用,结合以生物途径为基础的实验验证是一种阐释复方中药作用机制较为有效的方法,该方法的建立为复方中药的效应物质基础及作用机制研究起着积极作用。
Reduning injection is one of TCM injections for treatment of upper respiratory tract infection (URTI) from which is composed of Lonicerae japonicae Flos (Lonicera japonica), Gardeniae Fructus(Gardenia jasminoides), Artemisiae Annuae Herba(Artemisia annua). Clinical studies have revealed a variety of desirable pharmacological effects of Reduning injection on URTI, such as reducing of respiratory viral titres in the airway, suppressing the secretion of inflammatory cytokines (eg PGE2, IL-1, and ET), improving significantly the symptoms of URTI(eg, fever, cough, nasal congestion and sore throat). However, the molecular details about how Reduning injection can be administrated on URTI are still unclear. From the viewpoint of chemical structures, there is a high extent of overlap between Reduning compounds and western drug, which implies Reduning injection are a multi-component, multi-target agents at the molecular level. Therefore, it could be deduced that the therapeutic effectiveness of Reduning injection is achieved through collectively modulating the molecule network of biological systems by its active ingredients. Systems biology, especially network pharmacology, elucidates the underlying mechanisms of biological systems by depicting and studying the complex interactions at different level as various networks, which thus afford possibilities for uncovering the molecular mechanisms related to the therapeutic effect of tradition Chinese medicine. While virtual screening and network analysis provides powerful tools to predict the relationship of compound of TCM and target proteins interactions, to extract hidden information from large-scale data. Applying network pharmacology to the mode of action of Reduning may open up the possibility to understand the interactions the active ingredients in Reduning injection with these targets in the context of molecular networks. Firstly, the database of compound ligand in Reduning injection and target proteins related to URTI is constructed according to the pathogenesis of URTI and the information of the chemical components in Reduning injection. Subsequently, principal component analysis, molecular docking and network analysis were employed to elucidate the action mechanism of Reduning injection, the main active ingredient group and possible indications. According to these predicted results, the whole efficacy of a compound in a biological network is tested to evaluate the activity of its anti-inflammatory and anti-influenza virus molecular. Applying network pharmacology to study the action mechanism of Reduning injection is beneficial not only to our growing understanding of multi-components, multi-targets and multi-pathways mechanism of Reduning injection but also to exploit the molecular mechanism of traditional Chinese medicine.
All of the3D structure of the51proteins related to URTI and78chemicals in Reduning injection were obtained from PDB, Bestelin, UNPD database. The chemical molecules has good drug-like and better bioavailability compared with the38drugs for URTI from DrugBank by general purpose module of DiscoveryStudio2.5, and are likely to have some active compounds on URTI by PCA according to the chemical biology principle for similar chemical structure tending to show similar biological activities.
After a flexible docking between target proteins and78small molecules was achieved by Autodock4.0, the biological network was constructed by Cytoscape2.8.1including compounds with high docking scores(no less than5and higher than ligand), and then its topological features(network degree, betweenness, network density) were computed by NetworkAnalyzer, a plugin of Cytoscape2.8.1. These results suggest:a) there are25small molecules with a strong interaction with more than3target proteins, of which7chemical molecules with high betweenness target a large number of proteins(>=7) involving in viral replication, secretion of inflammatory mediators and intracellular signal transduction, suggesting that these molecules is of vital importance to Reduning injection for URTI; b) there are four bridging nodes(compounds) in D-D network which occupy critical sites in network and connect subregions to one another, implying that these molecules have the possible synergistic effect in Reduning injection; c) topological analysis of target proteins showed that the molecular mechanism of Reduning injection for URTI symptoms may be involved in inhibiting virus replication (influenza virus, rhinovirus, respiratory syncytial virus, etc.), reducing the secretion of inflammatory cytokines (IL-1, IL-6, NO, PGE2), regulating the MAPKs, PI3K-Akt, JAK-STAT, NF-κB signaling pathway.
The inhibition of compounds in Reduning injection on PGE2and NO from RAW264.7by LPS stimulation shows that of the collected28compounds, fifteen compounds significantly suppressed the production of PGE2of which8compounds share the activity of NO, and9compounds reduce cellular concentration of NO. While the predicted results show that, of these active compounds, the anti-inflammatory activities of9compounds might be the results from the suppression of the expression of COX, mPGES-1, iNOS through regulating MAPKs, JAK, NF-κB signaling pathway, and/or the inhibition of PLA2, COX, mPGES-1, iNOS enzyme activity.
To further verify the predicted results, Western blot was performed on LPS-induced RAW264.7to investigate the expression of COX-2, mPGES-1, iNOS. The result suggests that the protein expression levels of COX-2, mPGES-1, iNOS are inhibited by four compounds on LPS-induced RAW264.7cells of6compounds involving in regulating the MAPKs, JAK, NF-κB, signaling pathway.
Similarly, the anti-influenza activity of compounds in Reduning injection shows that RDN11was confirmed strong antiviral activity against influenza A virus(EC20=28.44μM, SI=24.66) through interacting with multiple stages of the influenza life cycle, such as HA, NA, SAH, IMP dehydrogenase. While network analysis shows that RDN14may interact with HA, IMP dehydrogenase protein and have little influence on the entire biological networks, similarly, RDN14was also confirm the weak inhibition of influenza A virus (EC50=91.284μM, SI=5.48). Basing on these experimental results, it is feasible to investigate the mode action of Reduning injection through the method that molecular docking and analysis is employed to predict the interaction between compounds and target proteins, and the results are tested by pathway-based experiment.
本文采用主成分分析、分子对接、网络分析以及体外细胞实验等方法对分析了热毒宁注射液中化学成分的空间结构分布、进行了化学分子和与URTI发病机制相关靶蛋白的分子对接,计算了靶蛋白与化学分子的相互作用网络特征,进而预测出热毒宁注射液治疗URTI的分子作用机制、主要活性成分群和可能的适应症,并从细胞水平和蛋白表达水平对所预测的热毒宁注射液抗炎、抗流感病毒分子机制进行了初步的试验验证。通过尝试运用网络药理学研究思路对热毒宁注射液治疗URTI的作用机制探索,明确了热毒宁注射液多组分、多靶点、多途径的作用机制,为其更好的临床应用提供理论支撑,也是对网络药理学在中药作用机制研究方面的有益探索。
1.热毒宁注射液化学分子和URTI靶蛋白数据库构建
根据URTI发病机制分析和前期热毒宁注射液化学成分的系统研究,通过TTD、 DrugBank、PDB、Bestelin、UNPD等数据库检索到含有原配体的51个靶蛋白晶体结构和58个化合物的78个化学分子的三维结构。利用DiscoveryStudio2.5中General Purpose对化学分子的分子描述符,并通过与已上市的用于治疗URTI的38个药物进行化学结构相似分析,发现热毒宁注射液中绝大部分化学成分具有较好的类药性和较好的生物利用度,其与治疗URTI的药物在化学结构上有较大的相似性,提示所选择的化合物包含了热毒宁注射液治疗URTI的活性化合物,同时也说明了热毒宁注射液中含有与治疗URTI相关的活性化合物。
2.热毒宁注射液分子对接与网络分析
应用Autodock计算化学分子与靶蛋白,再以原配体为阂值,取对接分值较高的化合物(score>=5)导入Cytoscape2.8.1构建生物网络,并通过网络特征分析(包括网络度、介数、网络密度等)发现：a)有25个化学分子与3个以上的靶蛋白存在较强相互作用,其中7个分子对网络的影响比较大(介数比较高),且与7个以上靶蛋白存在作用,而这些靶蛋白分布于病毒复制、炎症介质分泌以及胞内信号转导等环节,推测这些分子在热毒宁注射液治疗URTI中有极重要的地位；b)有4个小分子在分子-分子网络中处于桥连点的位置,有助于保证网络中不同模块间的信息流通,推测其在热毒宁注射液中与其它分子可能存在协同作用：c)靶点分析表明热毒宁注射液缓解URTI症状的分子机制可能是抑制病毒(流感病毒、鼻病毒以及呼吸道合胞病毒等)胞内复制、调控MAPKs、PI3K-Akt、JAK-STAT、 NF-kB信号通路、降低炎症因子(IL-1、 IL-6、NO、PGE2等)分泌,最终促进炎性机体恢复到平衡状态。
3.热毒宁注射液分子抗炎、抗病毒活性验证
通过测定热毒宁注射液中28个化合物对LPS刺激RAW264.7释放PGE2、NO的抑制作用,发现16个活性化合物(抑制率>=50%)；结合预测结果可知,其中9个可能是通过调控MAPKs、JAK、NF-kB信号通路影响COX、 mPGES-1、iNOS的表达或/和直接抑制PLA2、COX、mPGES-1、iNOS酶的活性来降低PGE2、NO含量,而进一步对COX-2、 mPGES-1、iNOS蛋白表达的分析发现在预测可调控MAPKs、JAK信号通路的(RDN3、 RDN4、 RDN5、RDN11、RDN18、RDN22、RDN27)7个化合物中,5个化合物(RDN3、 RDN5、RDN18、RDN22、RDN27)被证实其抑制PGE2、 NO分泌的作用与降低的COX-2、 mPGES-1、iNOS蛋白表达有关。
通过对热毒宁注射液中28个化合物的抗流感病毒实验发现,与HA、NA、SAH、IMP dehydrogenase等多个病毒复制环节蛋白存在相互作用的RDN11对A型流感病毒有较强的抑制活性(EC50=28.44μM, SI=24.66),而与HA、IMP dehydrogenase有相互作用但对整个生物网络影响较小的RDN14对A型流感病毒有较弱的抑制活性(EC50=91.284μM,SI=5.48)。
两次验证结果表明,基于网络药理学研究思路下的热毒宁注射液分子对接与网络分析预测中药分子与靶蛋白的相互作用,结合以生物途径为基础的实验验证是一种阐释复方中药作用机制较为有效的方法,该方法的建立为复方中药的效应物质基础及作用机制研究起着积极作用。
Reduning injection is one of TCM injections for treatment of upper respiratory tract infection (URTI) from which is composed of Lonicerae japonicae Flos (Lonicera japonica), Gardeniae Fructus(Gardenia jasminoides), Artemisiae Annuae Herba(Artemisia annua). Clinical studies have revealed a variety of desirable pharmacological effects of Reduning injection on URTI, such as reducing of respiratory viral titres in the airway, suppressing the secretion of inflammatory cytokines (eg PGE2, IL-1, and ET), improving significantly the symptoms of URTI(eg, fever, cough, nasal congestion and sore throat). However, the molecular details about how Reduning injection can be administrated on URTI are still unclear. From the viewpoint of chemical structures, there is a high extent of overlap between Reduning compounds and western drug, which implies Reduning injection are a multi-component, multi-target agents at the molecular level. Therefore, it could be deduced that the therapeutic effectiveness of Reduning injection is achieved through collectively modulating the molecule network of biological systems by its active ingredients. Systems biology, especially network pharmacology, elucidates the underlying mechanisms of biological systems by depicting and studying the complex interactions at different level as various networks, which thus afford possibilities for uncovering the molecular mechanisms related to the therapeutic effect of tradition Chinese medicine. While virtual screening and network analysis provides powerful tools to predict the relationship of compound of TCM and target proteins interactions, to extract hidden information from large-scale data. Applying network pharmacology to the mode of action of Reduning may open up the possibility to understand the interactions the active ingredients in Reduning injection with these targets in the context of molecular networks. Firstly, the database of compound ligand in Reduning injection and target proteins related to URTI is constructed according to the pathogenesis of URTI and the information of the chemical components in Reduning injection. Subsequently, principal component analysis, molecular docking and network analysis were employed to elucidate the action mechanism of Reduning injection, the main active ingredient group and possible indications. According to these predicted results, the whole efficacy of a compound in a biological network is tested to evaluate the activity of its anti-inflammatory and anti-influenza virus molecular. Applying network pharmacology to study the action mechanism of Reduning injection is beneficial not only to our growing understanding of multi-components, multi-targets and multi-pathways mechanism of Reduning injection but also to exploit the molecular mechanism of traditional Chinese medicine.
All of the3D structure of the51proteins related to URTI and78chemicals in Reduning injection were obtained from PDB, Bestelin, UNPD database. The chemical molecules has good drug-like and better bioavailability compared with the38drugs for URTI from DrugBank by general purpose module of DiscoveryStudio2.5, and are likely to have some active compounds on URTI by PCA according to the chemical biology principle for similar chemical structure tending to show similar biological activities.
After a flexible docking between target proteins and78small molecules was achieved by Autodock4.0, the biological network was constructed by Cytoscape2.8.1including compounds with high docking scores(no less than5and higher than ligand), and then its topological features(network degree, betweenness, network density) were computed by NetworkAnalyzer, a plugin of Cytoscape2.8.1. These results suggest:a) there are25small molecules with a strong interaction with more than3target proteins, of which7chemical molecules with high betweenness target a large number of proteins(>=7) involving in viral replication, secretion of inflammatory mediators and intracellular signal transduction, suggesting that these molecules is of vital importance to Reduning injection for URTI; b) there are four bridging nodes(compounds) in D-D network which occupy critical sites in network and connect subregions to one another, implying that these molecules have the possible synergistic effect in Reduning injection; c) topological analysis of target proteins showed that the molecular mechanism of Reduning injection for URTI symptoms may be involved in inhibiting virus replication (influenza virus, rhinovirus, respiratory syncytial virus, etc.), reducing the secretion of inflammatory cytokines (IL-1, IL-6, NO, PGE2), regulating the MAPKs, PI3K-Akt, JAK-STAT, NF-κB signaling pathway.
The inhibition of compounds in Reduning injection on PGE2and NO from RAW264.7by LPS stimulation shows that of the collected28compounds, fifteen compounds significantly suppressed the production of PGE2of which8compounds share the activity of NO, and9compounds reduce cellular concentration of NO. While the predicted results show that, of these active compounds, the anti-inflammatory activities of9compounds might be the results from the suppression of the expression of COX, mPGES-1, iNOS through regulating MAPKs, JAK, NF-κB signaling pathway, and/or the inhibition of PLA2, COX, mPGES-1, iNOS enzyme activity.
To further verify the predicted results, Western blot was performed on LPS-induced RAW264.7to investigate the expression of COX-2, mPGES-1, iNOS. The result suggests that the protein expression levels of COX-2, mPGES-1, iNOS are inhibited by four compounds on LPS-induced RAW264.7cells of6compounds involving in regulating the MAPKs, JAK, NF-κB, signaling pathway.
Similarly, the anti-influenza activity of compounds in Reduning injection shows that RDN11was confirmed strong antiviral activity against influenza A virus(EC20=28.44μM, SI=24.66) through interacting with multiple stages of the influenza life cycle, such as HA, NA, SAH, IMP dehydrogenase. While network analysis shows that RDN14may interact with HA, IMP dehydrogenase protein and have little influence on the entire biological networks, similarly, RDN14was also confirm the weak inhibition of influenza A virus (EC50=91.284μM, SI=5.48). Basing on these experimental results, it is feasible to investigate the mode action of Reduning injection through the method that molecular docking and analysis is employed to predict the interaction between compounds and target proteins, and the results are tested by pathway-based experiment.
引文
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