SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths.There are currently no registered therapies for treating coronavirus infections.Because of time consuming process of new drug dev...SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths.There are currently no registered therapies for treating coronavirus infections.Because of time consuming process of new drug development,drug repositioning may be the only solution to the epidemic of sudden infectious diseases.We systematically analyzed all the proteins encoded by SARS-CoV-2 genes,compared them with proteins from other coronavirnses,predicted their structures,and built 19 structures that could be done by homology modeling.By performing target-based virtual ligand screening,a total of21 targets(including two human targets)were screened against compound libraries including ZINC drug database and our own database of natural products.Structure and screening results of important targets such as 3-chymotrypsin-like protease(3 CLpro),Spike,RNA-dependent RNA polymerase(RdRp),and papain like protease(PLpro)were discussed in detail.In addition,a database of 78 commonly used antiviral drugs including those currently on the market and undergoing clinical trials for SARS-CoV-2 was constructed.Possible targets of these compounds and potential drugs acting on a certain target were predicted.This study will provide new lead compounds and targets for further in vitro and in vivo studies of SARS-CoV-2,new insights for those drugs currently ongoing clinical studies,and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.展开更多
MAP kinases transduce signals that are involved in a multitude of cellular pathways and functions in response to a variety of ligands and cell stimuli. Aberrant or inappropriate functions of MAPKs have now been identi...MAP kinases transduce signals that are involved in a multitude of cellular pathways and functions in response to a variety of ligands and cell stimuli. Aberrant or inappropriate functions of MAPKs have now been identified in diseases ranging from cancer to inflammatory disease to obesity and diabetes. In many cell types, the MAPKs ERK1/2 are linked to cell proliferation. ERK1/2 are thought to play a role in some cancers, because mutations in Ras and B-Raf, which can activate the ERK1/2 cascade, are found in many human tumors. Abnormal ERK1/2 signaling has also been found in polycystic kidney disease, and serious developmental disorders such as cardio-facio-cutaneous syndrome arise from mutations in components of the ERK1/2 cascade. ERK1/2 are essential in well-differentiated cells and have been linked to long-term potentiation in neurons and in maintenance of epithelial polarity. Additionally, ERK1/2 are important for insulin gene transcription in pancreatic beta cells, which produce insulin in response to increases in circulating glucose to permit efficient glucose utilization and storage in the organism. Nutrients and hormones that induce or repress insulin secretion activate and/or inhibit ERK1/2 in a manner that reflects the secretory demand on beta cells. Disturbances in this and other regulatory pathways may result in the contribution of ERK1/2 to the etiology of certain human disorders.展开更多
Lianhuaqingwen(LHQW)capsule,a herb medicine product,has been clinically proved to be effective in coronavirus disease 2019(COVID-19)pneumonia treatment.However,human exposure to LHQW components and their pharmacologic...Lianhuaqingwen(LHQW)capsule,a herb medicine product,has been clinically proved to be effective in coronavirus disease 2019(COVID-19)pneumonia treatment.However,human exposure to LHQW components and their pharmacological effects remain largely unknown.Hence,this study aimed to determine human exposure to LHQW components and their anti-COVID-19 pharmacological activities.Analysis of LHQW component profiles in human plasma and urine after repeated therapeutic dosing was conducted using a combination of HRMS and an untargeted data-mining approach,leading to detection of 132 LHQW prototype and metabolite components,which were absorbed via the gastrointestinal tract and formed via biotransformation in human,respectively.Together with data from screening by comprehensive 2 D angiotensin-converting enzyme 2(ACE2)biochromatography,8 components in LHQW that were exposed to human and had potential ACE2 targeting ability were identified for further pharmacodynamic evaluation.Results show that rhein,forsythoside A,forsythoside I,neochlorogenic acid and its isomers exhibited high inhibitory effect on ACE2.For the first time,this study provides chemical and biochemical evidence for exploring molecular mechanisms of therapeutic effects of LHQW capsule for the treatment of COVID-19 patients based on the components exposed to human.It also demonstrates the utility of the human exposure-based approach to identify pharmaceutically active components in Chinese herb medicines.展开更多
目的:采用网络药理学方法对用于妇科血瘀证原发性痛经的四物汤类方主要活性成分的分子作用机制分析,探索其多成分-多靶点-多通路相关关系。方法:针对类方中藁本内酯、正丁烯基酜内酯、川芎内酯、阿魏酸、没食子酸、芍药苷、焦地黄素A、...目的:采用网络药理学方法对用于妇科血瘀证原发性痛经的四物汤类方主要活性成分的分子作用机制分析,探索其多成分-多靶点-多通路相关关系。方法:针对类方中藁本内酯、正丁烯基酜内酯、川芎内酯、阿魏酸、没食子酸、芍药苷、焦地黄素A、梓醇等共有的活性成分及各方差异的代表性活性成分,依据PharmMapper数据库构建多成分-蛋白网络,获取的靶点信息利用Kyoto encyclopedia of genes and genomes(KEGG)通路数据库,采用Cytoscape软件建立四物汤类方成分-靶点-通路网络模型。结果与结论:网络分析表明,在细胞过程中起重要作用的丝氨酸苏氨酸蛋白激酶是四物汤及其类方共有的潜在作用靶点群;四物汤主要活性成分涉及神经-内分泌-免疫等相关的51条通路,除与四物汤相同的通路外,少腹逐瘀汤偏重于脂质代谢;香附四物汤偏重于氨基酸代谢通路;桃红四物汤偏重于碳水化合物代谢;芩连四物汤偏重于ErbB,VEGF信号转导通路。四物汤及衍化方既有共同的作用靶点及通路,又各有偏重,体现了方剂多成分、多靶点、多途径作用模式,该研究为深入研究四物汤类方分子作用机制提供线索。展开更多
Objective: In this study we execute a rational screen to identify Chinese medical herbs that are commonly used in treating viral respiratory infections and also contain compounds that might directly inhibit 2019 novel...Objective: In this study we execute a rational screen to identify Chinese medical herbs that are commonly used in treating viral respiratory infections and also contain compounds that might directly inhibit 2019 novel coronavirus(2019-nCoV), an ongoing novel coronavirus that causes pneumonia.Methods: There were two main steps in the screening process. In the first step we conducted a literature search for natural compounds that had been biologically confirmed as against sever acute respiratory syndrome coronavirus or Middle East respiratory syndrome coronavirus. Resulting compounds were cross-checked for listing in the Traditional Chinese Medicine Systems Pharmacology Database.Compounds meeting both requirements were subjected to absorption, distribution, metabolism and excretion(ADME) evaluation to verify that oral administration would be effective. Next, a docking analysis was used to test whether the compound had the potential for direct 2019-nCoV protein interaction.In the second step we searched Chinese herbal databases to identify plants containing the selected compounds. Plants containing 2 or more of the compounds identified in our screen were then checked against the catalogue for classic herbal usage. Finally, network pharmacology analysis was used to predict the general in vivo effects of each selected herb.Results: Of the natural compounds screened, 13 that exist in traditional Chinese medicines were also found to have potential anti-2019-nCoV activity. Further, 125 Chinese herbs were found to contain 2 or more of these 13 compounds. Of these 125 herbs, 26 are classically catalogued as treating viral respiratory infections. Network pharmacology analysis predicted that the general in vivo roles of these26 herbal plants were related to regulating viral infection, immune/inflammation reactions and hypoxia response.Conclusion: Chinese herbal treatments classically used for treating viral respiratory infection might contain direct anti-2019-nCoV compounds.展开更多
The recent pandemic of coronavirus disease 2019(COVID-19)caused by SARS-CoV-2 has raised global health concerns.The viral 3-chymotrypsin-like cysteine protease(3CL^pro)enzyme controls coronavirus replication and is es...The recent pandemic of coronavirus disease 2019(COVID-19)caused by SARS-CoV-2 has raised global health concerns.The viral 3-chymotrypsin-like cysteine protease(3CL^pro)enzyme controls coronavirus replication and is essential for its life cycle.3CL^pro is a proven drug discovery target in the case of severe acute respiratory syndrome coronavirus(SARS-CoV)and Middle East respiratory syndrome coronavirus(MERS-CoV).Recent studies revealed that the genome sequence of SARS-CoV-2 is very similar to that of SARS-CoV.Therefore,herein,we analysed the 3CL^pro sequence,constructed its 3D homology model,and screened it against a medicinal plant library containing 32,297 potential anti-viral phytochemicals/traditional Chinese medicinal compounds.Our analyses revealed that the top nine hits might serve as potential anti-SARS-CoV-2 lead molecules for further optimisation and drug development process to combat COVID-19.展开更多
The effects of tanshinone IIA on the proliferation of the human non-small cell lung cancer cell line A549 and its possible mechanism on the VEGFNEGFR signal pathway were investigated. The exploration of the interactio...The effects of tanshinone IIA on the proliferation of the human non-small cell lung cancer cell line A549 and its possible mechanism on the VEGFNEGFR signal pathway were investigated. The exploration of the interaction between tanshinone IIA and its target proteins provides a feasible platform for studying the anticancer mechanism of active components of herbs. The CCK-8 assay was used to evaluate the proliferative activity of A549 cells treated with tanshinone IIA (2.5-80 mu mol/E) for 24, 48 and 72 h, respectively. Flow cytometry was used for the detection of cell apoptosis and cell cycle perturbation. VEGF and VEGFR2 expression were studied by Western blotting. The binding mode of tanshinone IIA within the crystal stmcture of the VEGFR2 protein was evaluated with molecular docking analysis by use of the CDOCKER algorithm in Discovery Studio 2.1. The CCK-8 results showed that tanshinone IIA can significantly inhibit A549 cell proliferation in a dose- and time-dependent manner. Flow cytometry results showed that the apoptosis rate of tested group was higher than the vehicle control, and tanshinone IIA-treated cells accumulated at the S phase, which was higher than the vehicle control. Furthermore, the expression of VEGF and VEGFR2 was decreased in Western blot Finally, molecular docking analysis revealed that tanshinone IIA could be stably docked into the kinase domain of VEGFR2 protein with its unique modes to form H-bonds with Cys917 and pi-pi stacking interactions with Va1848. In conclusion, tanshinone IIA may suppress A549 proliferation, induce apoptosis and cell cycle arrest at the S phase. This drug may suppress angiogenesis by targeting the protein kinase domains of VEGF/VEGFR2. (C) 2015 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.展开更多
多靶点药物能同时调节多靶点、调节疾病网络的多个环节,在获得较高疗效的同时可降低单靶点引起的毒副作用,是治疗复杂性疾病的理想药物,因此已成为药物研发的主要方向。而天然产物凭借其结构的多样性,较高的多靶点活性和较小的毒副作用...多靶点药物能同时调节多靶点、调节疾病网络的多个环节,在获得较高疗效的同时可降低单靶点引起的毒副作用,是治疗复杂性疾病的理想药物,因此已成为药物研发的主要方向。而天然产物凭借其结构的多样性,较高的多靶点活性和较小的毒副作用等优势,是多靶点药物开发的重要来源。计算机辅助药物设计(computer-aided drug design,CADD)是常用的多靶点药物研发方法,其主要包括虚拟筛选和药效团设计。该文对其进行了系统梳理,探讨了各方法用于天然产物多靶点药物研发的前景与优势。展开更多
Naodesheng(NDS) formula, which consists of Rhizoma Chuanxiong, Lobed Kudzuvine, Carthamus tinctorius, Radix Notoginseng, and Crataegus pinnatifida, is widely applied for the treatment of cardio/cerebrovascular ischemi...Naodesheng(NDS) formula, which consists of Rhizoma Chuanxiong, Lobed Kudzuvine, Carthamus tinctorius, Radix Notoginseng, and Crataegus pinnatifida, is widely applied for the treatment of cardio/cerebrovascular ischemic diseases, ischemic stroke, and sequelae of cerebral hemorrhage, etc. At present, the studies on NDS formula for Alzheimer's disease(AD) only focus on single component of this prescription, and there is no report about the synergistic mechanism of the constituents in NDS formula for the potential treatment of dementia. Therefore, the present study aimed to predict the potential targets and uncover the mechanisms of NDS formula for the treatment of AD. Firstly, we collected the constituents in NDS formula and key targets toward AD. Then, drug-likeness, oral bioavailability, and blood-brain barrier permeability were evaluated to find drug-like and lead-like constituents for treatment of central nervous system diseases. By combining the advantages of machine learning, molecular docking, and pharmacophore mapping, we attempted to predict the targets of constituents and find potential multi-target compounds from NDS formula. Finally, we built constituent-target network, constituent-target-target network and target-biological pathway network to study the network pharmacology of the constituents in NDS formula. To the best of our knowledge, this represented the first to study the mechanism of NDS formula for potential efficacy for AD treatment by means of the virtual screening and network pharmacology methods.展开更多
In this study, molecular interactions of the ligands, quercetin, gallic acid, and metformin with various diabetes mellitus-related protein targets, such as glycogen phosphorylase and peroxisome proliferatoractivated r...In this study, molecular interactions of the ligands, quercetin, gallic acid, and metformin with various diabetes mellitus-related protein targets, such as glycogen phosphorylase and peroxisome proliferatoractivated receptor gamma, were assessed. It was revealed that quercetin possesses good binding affinity to both targets. Quercetin is a major constituent of methanolic extracts of Phyllanthus emblica fruit. The antihyperglycemic effect of quercetin in streptozotocin(STZ)-induced diabetic rats was examined. The isolated quercetin administered at a dose of 75 mg/kg body weight produced a maximum decrease of14.78% in blood glucose levels in the diabetic rats after 7 days of treatment. Furthermore, quercetin doses of 50 and 75 mg/kg were shown to significantly improve the profiles of triglycerides, high-density lipoprotein, very-low-density lipoprotein, low-density lipoprotein, and total cholesterol at the end of the study in STZ-induced diabetic rats. The administration of quercetin(25, 50, and 75 mg/kg body weight)daily for 28 days in STZ-induced diabetic rats resulted in a significant decrease in blood glucose and urine sugar levels, with a considerable rise in plasma insulin and hemoglobin levels. Therefore, quercetin is a potential drug with antidiabetic and antihyperglycemic action mediated by changes in the levels of glucose, cholesterol, and triglycerides as indicated by in silico and in vivo studies.展开更多
In this paper, a three-dimensional quantitative structure-activity relationships(3 D-QSAR) study for 20 HIV-1 reverse transcriptase(RT) inhibitors was established using Topomer Co MFA. The models were built based on d...In this paper, a three-dimensional quantitative structure-activity relationships(3 D-QSAR) study for 20 HIV-1 reverse transcriptase(RT) inhibitors was established using Topomer Co MFA. The models were built based on different fragment cutting models, with the most effective model of the multiple correlation coefficients of fitting(r^2) to be 0.920, cross-validation(q^2) of 0.575, and external validation(Q_(ext)~2) being 0.701. The results indicated that the model obtained has both favorable estimation stability and good prediction capability. Topomer Search was used to search R-group from ZINC database. As a result, a series of R-groups with relatively high activity contribution was obtained. By No. 6 molecule filtering, 3 R_1 and 15 R_2 groups were selected, and employed to alternately substitute for the R_1 and R_2 of sample 6. Finally, 45 new compounds were designed, and the Topomer CoMFA model was used to predicate the biological activity, so the Topomer Search is effective in screening and can guide the design of new HIV/AIDS drugs. The molecular docking method was also used to study the interactions of these drugs by docking the ligands into HIV-1 RT active site, which revealed the likely bioactive conformations. This study showed that there are extensive interactions between the 1,3,4-thiazolidinone revertase inhibitors and His84, Asp145, Lys33 and Leu83 residues in the active site of HIV-1 RT. These results provide useful insights for the design of potent new inhibitors of RT.展开更多
基金support from National Mega-project for Innovative Drugs(grant number 2019ZX09721001-004-007,China)National Natural Science Foundation of China(NSFC,grant numbers U1803122,81773637,81773594,and U1703111)the Fundamental Research Fund for the Central Universities(HUST COVID-19 Rapid Response Call,No.2020kfyXGYJ037,China)
文摘SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths.There are currently no registered therapies for treating coronavirus infections.Because of time consuming process of new drug development,drug repositioning may be the only solution to the epidemic of sudden infectious diseases.We systematically analyzed all the proteins encoded by SARS-CoV-2 genes,compared them with proteins from other coronavirnses,predicted their structures,and built 19 structures that could be done by homology modeling.By performing target-based virtual ligand screening,a total of21 targets(including two human targets)were screened against compound libraries including ZINC drug database and our own database of natural products.Structure and screening results of important targets such as 3-chymotrypsin-like protease(3 CLpro),Spike,RNA-dependent RNA polymerase(RdRp),and papain like protease(PLpro)were discussed in detail.In addition,a database of 78 commonly used antiviral drugs including those currently on the market and undergoing clinical trials for SARS-CoV-2 was constructed.Possible targets of these compounds and potential drugs acting on a certain target were predicted.This study will provide new lead compounds and targets for further in vitro and in vivo studies of SARS-CoV-2,new insights for those drugs currently ongoing clinical studies,and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.
文摘MAP kinases transduce signals that are involved in a multitude of cellular pathways and functions in response to a variety of ligands and cell stimuli. Aberrant or inappropriate functions of MAPKs have now been identified in diseases ranging from cancer to inflammatory disease to obesity and diabetes. In many cell types, the MAPKs ERK1/2 are linked to cell proliferation. ERK1/2 are thought to play a role in some cancers, because mutations in Ras and B-Raf, which can activate the ERK1/2 cascade, are found in many human tumors. Abnormal ERK1/2 signaling has also been found in polycystic kidney disease, and serious developmental disorders such as cardio-facio-cutaneous syndrome arise from mutations in components of the ERK1/2 cascade. ERK1/2 are essential in well-differentiated cells and have been linked to long-term potentiation in neurons and in maintenance of epithelial polarity. Additionally, ERK1/2 are important for insulin gene transcription in pancreatic beta cells, which produce insulin in response to increases in circulating glucose to permit efficient glucose utilization and storage in the organism. Nutrients and hormones that induce or repress insulin secretion activate and/or inhibit ERK1/2 in a manner that reflects the secretory demand on beta cells. Disturbances in this and other regulatory pathways may result in the contribution of ERK1/2 to the etiology of certain human disorders.
基金supported by Natural Science Foundation of China,China,(Grant Nos.81773688,U1903119,81973291,and 81973275)Zhejiang University Special Scientific Research Fund for COVID-19 Prevention and Control,China+1 种基金“Phospherus”Project of Shanghai Science and Technology Committee,China,(Grant Nos.19QA1411500)National Major Scientific and Technological Special Project for"Significant New Drugs Development",China,(Grant No.2020ZX09201005)
文摘Lianhuaqingwen(LHQW)capsule,a herb medicine product,has been clinically proved to be effective in coronavirus disease 2019(COVID-19)pneumonia treatment.However,human exposure to LHQW components and their pharmacological effects remain largely unknown.Hence,this study aimed to determine human exposure to LHQW components and their anti-COVID-19 pharmacological activities.Analysis of LHQW component profiles in human plasma and urine after repeated therapeutic dosing was conducted using a combination of HRMS and an untargeted data-mining approach,leading to detection of 132 LHQW prototype and metabolite components,which were absorbed via the gastrointestinal tract and formed via biotransformation in human,respectively.Together with data from screening by comprehensive 2 D angiotensin-converting enzyme 2(ACE2)biochromatography,8 components in LHQW that were exposed to human and had potential ACE2 targeting ability were identified for further pharmacodynamic evaluation.Results show that rhein,forsythoside A,forsythoside I,neochlorogenic acid and its isomers exhibited high inhibitory effect on ACE2.For the first time,this study provides chemical and biochemical evidence for exploring molecular mechanisms of therapeutic effects of LHQW capsule for the treatment of COVID-19 patients based on the components exposed to human.It also demonstrates the utility of the human exposure-based approach to identify pharmaceutically active components in Chinese herb medicines.
文摘目的:采用网络药理学方法对用于妇科血瘀证原发性痛经的四物汤类方主要活性成分的分子作用机制分析,探索其多成分-多靶点-多通路相关关系。方法:针对类方中藁本内酯、正丁烯基酜内酯、川芎内酯、阿魏酸、没食子酸、芍药苷、焦地黄素A、梓醇等共有的活性成分及各方差异的代表性活性成分,依据PharmMapper数据库构建多成分-蛋白网络,获取的靶点信息利用Kyoto encyclopedia of genes and genomes(KEGG)通路数据库,采用Cytoscape软件建立四物汤类方成分-靶点-通路网络模型。结果与结论:网络分析表明,在细胞过程中起重要作用的丝氨酸苏氨酸蛋白激酶是四物汤及其类方共有的潜在作用靶点群;四物汤主要活性成分涉及神经-内分泌-免疫等相关的51条通路,除与四物汤相同的通路外,少腹逐瘀汤偏重于脂质代谢;香附四物汤偏重于氨基酸代谢通路;桃红四物汤偏重于碳水化合物代谢;芩连四物汤偏重于ErbB,VEGF信号转导通路。四物汤及衍化方既有共同的作用靶点及通路,又各有偏重,体现了方剂多成分、多靶点、多途径作用模式,该研究为深入研究四物汤类方分子作用机制提供线索。
基金supported by Shanghai Leading Talent Grants in Medicine(No.2019LG26)Shanghai Traditional Chinese Medicine Content Construction Innovation Project(No.ZY3-CCCX-3-7001)Postdoctoral Funding of Shanghai Gongil Hospital(No.GLBH2017002).
文摘Objective: In this study we execute a rational screen to identify Chinese medical herbs that are commonly used in treating viral respiratory infections and also contain compounds that might directly inhibit 2019 novel coronavirus(2019-nCoV), an ongoing novel coronavirus that causes pneumonia.Methods: There were two main steps in the screening process. In the first step we conducted a literature search for natural compounds that had been biologically confirmed as against sever acute respiratory syndrome coronavirus or Middle East respiratory syndrome coronavirus. Resulting compounds were cross-checked for listing in the Traditional Chinese Medicine Systems Pharmacology Database.Compounds meeting both requirements were subjected to absorption, distribution, metabolism and excretion(ADME) evaluation to verify that oral administration would be effective. Next, a docking analysis was used to test whether the compound had the potential for direct 2019-nCoV protein interaction.In the second step we searched Chinese herbal databases to identify plants containing the selected compounds. Plants containing 2 or more of the compounds identified in our screen were then checked against the catalogue for classic herbal usage. Finally, network pharmacology analysis was used to predict the general in vivo effects of each selected herb.Results: Of the natural compounds screened, 13 that exist in traditional Chinese medicines were also found to have potential anti-2019-nCoV activity. Further, 125 Chinese herbs were found to contain 2 or more of these 13 compounds. Of these 125 herbs, 26 are classically catalogued as treating viral respiratory infections. Network pharmacology analysis predicted that the general in vivo roles of these26 herbal plants were related to regulating viral infection, immune/inflammation reactions and hypoxia response.Conclusion: Chinese herbal treatments classically used for treating viral respiratory infection might contain direct anti-2019-nCoV compounds.
基金This work was supported by the National Key Research and Development Program of China(2020YFC0845600)the Hubei Provincial Natural Science Foundation of China(2019CFA014)+1 种基金the Starting Research Grant for High-level Talents from Guangxi University,Nanning,ChinaPostdoctoral Research Platform Grant of Guangxi University,Nanning,China.
文摘The recent pandemic of coronavirus disease 2019(COVID-19)caused by SARS-CoV-2 has raised global health concerns.The viral 3-chymotrypsin-like cysteine protease(3CL^pro)enzyme controls coronavirus replication and is essential for its life cycle.3CL^pro is a proven drug discovery target in the case of severe acute respiratory syndrome coronavirus(SARS-CoV)and Middle East respiratory syndrome coronavirus(MERS-CoV).Recent studies revealed that the genome sequence of SARS-CoV-2 is very similar to that of SARS-CoV.Therefore,herein,we analysed the 3CL^pro sequence,constructed its 3D homology model,and screened it against a medicinal plant library containing 32,297 potential anti-viral phytochemicals/traditional Chinese medicinal compounds.Our analyses revealed that the top nine hits might serve as potential anti-SARS-CoV-2 lead molecules for further optimisation and drug development process to combat COVID-19.
基金supported by the National Natural Science Foundation of China(No.81274135)
文摘The effects of tanshinone IIA on the proliferation of the human non-small cell lung cancer cell line A549 and its possible mechanism on the VEGFNEGFR signal pathway were investigated. The exploration of the interaction between tanshinone IIA and its target proteins provides a feasible platform for studying the anticancer mechanism of active components of herbs. The CCK-8 assay was used to evaluate the proliferative activity of A549 cells treated with tanshinone IIA (2.5-80 mu mol/E) for 24, 48 and 72 h, respectively. Flow cytometry was used for the detection of cell apoptosis and cell cycle perturbation. VEGF and VEGFR2 expression were studied by Western blotting. The binding mode of tanshinone IIA within the crystal stmcture of the VEGFR2 protein was evaluated with molecular docking analysis by use of the CDOCKER algorithm in Discovery Studio 2.1. The CCK-8 results showed that tanshinone IIA can significantly inhibit A549 cell proliferation in a dose- and time-dependent manner. Flow cytometry results showed that the apoptosis rate of tested group was higher than the vehicle control, and tanshinone IIA-treated cells accumulated at the S phase, which was higher than the vehicle control. Furthermore, the expression of VEGF and VEGFR2 was decreased in Western blot Finally, molecular docking analysis revealed that tanshinone IIA could be stably docked into the kinase domain of VEGFR2 protein with its unique modes to form H-bonds with Cys917 and pi-pi stacking interactions with Va1848. In conclusion, tanshinone IIA may suppress A549 proliferation, induce apoptosis and cell cycle arrest at the S phase. This drug may suppress angiogenesis by targeting the protein kinase domains of VEGF/VEGFR2. (C) 2015 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
文摘多靶点药物能同时调节多靶点、调节疾病网络的多个环节,在获得较高疗效的同时可降低单靶点引起的毒副作用,是治疗复杂性疾病的理想药物,因此已成为药物研发的主要方向。而天然产物凭借其结构的多样性,较高的多靶点活性和较小的毒副作用等优势,是多靶点药物开发的重要来源。计算机辅助药物设计(computer-aided drug design,CADD)是常用的多靶点药物研发方法,其主要包括虚拟筛选和药效团设计。该文对其进行了系统梳理,探讨了各方法用于天然产物多靶点药物研发的前景与优势。
基金supported by the Research Special Fund for the National Great Science and Technology Projects(No.2012ZX09301002-001-001)the International Collaboration Project(No.2011DFR31240)Peking Union Medical College graduate student innovation fund(No.2013-1007-18)
文摘Naodesheng(NDS) formula, which consists of Rhizoma Chuanxiong, Lobed Kudzuvine, Carthamus tinctorius, Radix Notoginseng, and Crataegus pinnatifida, is widely applied for the treatment of cardio/cerebrovascular ischemic diseases, ischemic stroke, and sequelae of cerebral hemorrhage, etc. At present, the studies on NDS formula for Alzheimer's disease(AD) only focus on single component of this prescription, and there is no report about the synergistic mechanism of the constituents in NDS formula for the potential treatment of dementia. Therefore, the present study aimed to predict the potential targets and uncover the mechanisms of NDS formula for the treatment of AD. Firstly, we collected the constituents in NDS formula and key targets toward AD. Then, drug-likeness, oral bioavailability, and blood-brain barrier permeability were evaluated to find drug-like and lead-like constituents for treatment of central nervous system diseases. By combining the advantages of machine learning, molecular docking, and pharmacophore mapping, we attempted to predict the targets of constituents and find potential multi-target compounds from NDS formula. Finally, we built constituent-target network, constituent-target-target network and target-biological pathway network to study the network pharmacology of the constituents in NDS formula. To the best of our knowledge, this represented the first to study the mechanism of NDS formula for potential efficacy for AD treatment by means of the virtual screening and network pharmacology methods.
基金the DST-SERB Major Research Project,New Delhi,India[Project File No.SB/YS/LS-109/2014]for funding this projectthe Management of A.V.V.M.Sri Pushpam College(Autonomous)+1 种基金Poondi,and Sharmila Institute of Medicinal Products Research Academy(SIMPRA)Thanjavur,India,for providing necessary facilities and support in carrying out this work
文摘In this study, molecular interactions of the ligands, quercetin, gallic acid, and metformin with various diabetes mellitus-related protein targets, such as glycogen phosphorylase and peroxisome proliferatoractivated receptor gamma, were assessed. It was revealed that quercetin possesses good binding affinity to both targets. Quercetin is a major constituent of methanolic extracts of Phyllanthus emblica fruit. The antihyperglycemic effect of quercetin in streptozotocin(STZ)-induced diabetic rats was examined. The isolated quercetin administered at a dose of 75 mg/kg body weight produced a maximum decrease of14.78% in blood glucose levels in the diabetic rats after 7 days of treatment. Furthermore, quercetin doses of 50 and 75 mg/kg were shown to significantly improve the profiles of triglycerides, high-density lipoprotein, very-low-density lipoprotein, low-density lipoprotein, and total cholesterol at the end of the study in STZ-induced diabetic rats. The administration of quercetin(25, 50, and 75 mg/kg body weight)daily for 28 days in STZ-induced diabetic rats resulted in a significant decrease in blood glucose and urine sugar levels, with a considerable rise in plasma insulin and hemoglobin levels. Therefore, quercetin is a potential drug with antidiabetic and antihyperglycemic action mediated by changes in the levels of glucose, cholesterol, and triglycerides as indicated by in silico and in vivo studies.
基金supported by the National Natural Science Foundation of China(21475081,21275094)the Graduate Innovation Fund of Shaanxi University of Science and Technology
文摘In this paper, a three-dimensional quantitative structure-activity relationships(3 D-QSAR) study for 20 HIV-1 reverse transcriptase(RT) inhibitors was established using Topomer Co MFA. The models were built based on different fragment cutting models, with the most effective model of the multiple correlation coefficients of fitting(r^2) to be 0.920, cross-validation(q^2) of 0.575, and external validation(Q_(ext)~2) being 0.701. The results indicated that the model obtained has both favorable estimation stability and good prediction capability. Topomer Search was used to search R-group from ZINC database. As a result, a series of R-groups with relatively high activity contribution was obtained. By No. 6 molecule filtering, 3 R_1 and 15 R_2 groups were selected, and employed to alternately substitute for the R_1 and R_2 of sample 6. Finally, 45 new compounds were designed, and the Topomer CoMFA model was used to predicate the biological activity, so the Topomer Search is effective in screening and can guide the design of new HIV/AIDS drugs. The molecular docking method was also used to study the interactions of these drugs by docking the ligands into HIV-1 RT active site, which revealed the likely bioactive conformations. This study showed that there are extensive interactions between the 1,3,4-thiazolidinone revertase inhibitors and His84, Asp145, Lys33 and Leu83 residues in the active site of HIV-1 RT. These results provide useful insights for the design of potent new inhibitors of RT.
