PPARγis a peroxisome proliferator-activated receptor(PPAR)family protein and is a target for type 2 diabetes(T2D).In this paper,we have performed a molecular docking analysis between ligand molecules(CID9816265,CID11...PPARγis a peroxisome proliferator-activated receptor(PPAR)family protein and is a target for type 2 diabetes(T2D).In this paper,we have performed a molecular docking analysis between ligand molecules(CID9816265,CID11608015,CID20251380,CID20251343,CID20556263,CID624491,CID42609928,and CID86287562)and PPARγto determine the ligand specificity.It also helps to understand the ligand-binding domain(LBD)activity of PPARγduring the binding of the ligand.Further,a molecular dynamics simulation study was performed to determine the ligand biding stability in the PPARγLBD.Its ligand specificity informed us about the potentiality of selecting a partial agonist.The study also shows the binding conformation of Ceramicine B having hydrogen bonding affinity with a tricyclic polar head and stabilized theβ-sheet region.On the other hand,the tricyclic polar head of nimbolide also formed hydrogen bonding(Ser342),but it shows a lesser degree of stabilization in theβ-sheet region.It shows the binding conformation of partial agonist(PPARγ)in the Pocket-II of PPARγLBD,which has a significant role in stabilizing theβ-sheet region.It might help to regulate ERK/Cdk5 mediated phosphorylation of Ser245.The study helps us understand the valid pose of a set of ligands confirmation and target protein conformation using docking and molecular dynamics study.This in silico study will also help to initiate a drug discovery process of T2D.展开更多
Background: 5-HT4receptors in cortex and hippocampus area are considered as a possible target for modulation of cognitive functions in Alzheimer’s disease (AD). A systems pharmacology approach was adopted to evaluate...Background: 5-HT4receptors in cortex and hippocampus area are considered as a possible target for modulation of cognitive functions in Alzheimer’s disease (AD). A systems pharmacology approach was adopted to evaluate the potential of the 5-HT4 modulation in providing beneficialeffects on cognition in AD. Methods: A serotonergic synaptic cleft model was developed by integrating serotonin firing, release, synaptic half-life, drug/tracer properties (affinity and agonism) as inputs and5-HT4 activity as output. The serotonergic model was calibrated using bothinvivo data on free 5-HT levels in preclinical models and human imaging data. The model was further expanded to other neurontransmitter systems and incorporated into a computer-based cortical network model which implemented the physiology of 12 different membrane CNS targets. A biophysically realistic, multi-compartment model of 80 pyramidal cells and 40 interneurons was further calibrated usingdata reported for working memory tasks in healthyhumans and schizophrenia patients. Model output was the duration of the network firing activity in response to an external stimulus. Alzheimer’s disease (AD) pathology, in particular synapse and neuronal cell loss in addition to cholinergic deficits, was calibrated to align with the natural clinical disease progression. The model was used to provide insights into the effect of 5-HT4 activation on working memory and to prospectively simulate the response of PF- 04995274, a 5-HT4partial agonist, in a scopolamine-reversal trial in healthy human subjects. Results: The model output suggested a beneficial effect of 5-HT4 agonism on working memory. The model also projected no effect or an exacerbation of scopolamine impairment for low in- trinsic activity 5-HT4agonists, which was supported by the subsequent human trial outcome. The clinical prediction of the disease model strongly suggests that 5-HT4 agonists with high intrinsic activity may have a beneficial effect on cognition in AD patients.展开更多
A-α-CAO induces weak analgesia with very short duration in mice and is able to antagonize the analgesic effect of morphine (Mor) up to 3—4 days after a single injection. No tendency of dependence has been observed. ...A-α-CAO induces weak analgesia with very short duration in mice and is able to antagonize the analgesic effect of morphine (Mor) up to 3—4 days after a single injection. No tendency of dependence has been observed. It acts as a partial agonist on MVD with Ke value of 9×10^(-9) mol/L. Its antagonist effect remains after several washes and its agonist effect cannot be reversed by naloxone (Nx), provided the incubation time or the concentration of the agent is sufficient. On isolated GPI, A-α-CAO is a pure agonist with IC_(50) of 5.7×10^(-10) mol/L; this agonist effect cannot be removed by washing but can be reversed by Nx. On RVD and RbVD, it has antagonist effect against β-endorphine (β-end) and US0488H, which cannot be washed out easily, and the pA_2are 7.5 and 7.6 respectively. A-α-CAO also inhibits the specific binding of ~3H-etorphine (~3H-Etor) to the P_2 fraction of the mouse brain membrane with an IC_(30) of 3.2×10^(-9) mol/L. The inhibition on the high affinity binding sites of ~3H-Etor remains 95％ even after 6 washes.展开更多
目的:荟萃分析方法评价5-羟色胺(5-HT)1A受体部分激动剂治疗功能性消化不良(FD)的临床疗效及安全性。方法:计算机检索PubMed、Web of Science、CNKI等数据库建库起公开发表的5-HT1A受体部分激动剂治疗FD的随机对照研究(RCT)。RevMan 5....目的:荟萃分析方法评价5-羟色胺(5-HT)1A受体部分激动剂治疗功能性消化不良(FD)的临床疗效及安全性。方法:计算机检索PubMed、Web of Science、CNKI等数据库建库起公开发表的5-HT1A受体部分激动剂治疗FD的随机对照研究(RCT)。RevMan 5.4软件对纳入的资料荟萃分析,并进行亚组分析、分层分析,评价5-HT1A受体部分激动剂对FD的疗效及安全性。结果:纳入19项RCT,共计1575例患者(治疗组801例,对照组774例)。荟萃分析显示:治疗组总有效率高于对照组(OR=4.18,95%CI:3.05~5.73,P<0.00001),而消化道症状评分(SMD=-1.30,95%CI:-1.95~-0.64,P=0.0001)、焦虑状态评分(SMD=-1.22,95%CI:-1.79~-0.65,P<0.0001)和抑郁状态评分(SMD=-1.52,95%CI:-2.41~-0.63,P=0.0008)均低于对照组,嗜睡(OR=4.78,95%CI:1.80~12.70,P<0.05)、口干(OR=3.07,95%CI:1.31~7.19,P<0.05)发生率均高于对照组。结论:与常规或安慰剂治疗相比,联合应用5-HT1A受体部分激动剂能提高总体疗效,但嗜睡及口干发生率较高。展开更多
基金supported by Hallym University Research Fund and by Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education(NRF-2020R1C1C1008694&NRF-2020R1I1A3074575).
文摘PPARγis a peroxisome proliferator-activated receptor(PPAR)family protein and is a target for type 2 diabetes(T2D).In this paper,we have performed a molecular docking analysis between ligand molecules(CID9816265,CID11608015,CID20251380,CID20251343,CID20556263,CID624491,CID42609928,and CID86287562)and PPARγto determine the ligand specificity.It also helps to understand the ligand-binding domain(LBD)activity of PPARγduring the binding of the ligand.Further,a molecular dynamics simulation study was performed to determine the ligand biding stability in the PPARγLBD.Its ligand specificity informed us about the potentiality of selecting a partial agonist.The study also shows the binding conformation of Ceramicine B having hydrogen bonding affinity with a tricyclic polar head and stabilized theβ-sheet region.On the other hand,the tricyclic polar head of nimbolide also formed hydrogen bonding(Ser342),but it shows a lesser degree of stabilization in theβ-sheet region.It shows the binding conformation of partial agonist(PPARγ)in the Pocket-II of PPARγLBD,which has a significant role in stabilizing theβ-sheet region.It might help to regulate ERK/Cdk5 mediated phosphorylation of Ser245.The study helps us understand the valid pose of a set of ligands confirmation and target protein conformation using docking and molecular dynamics study.This in silico study will also help to initiate a drug discovery process of T2D.
文摘Background: 5-HT4receptors in cortex and hippocampus area are considered as a possible target for modulation of cognitive functions in Alzheimer’s disease (AD). A systems pharmacology approach was adopted to evaluate the potential of the 5-HT4 modulation in providing beneficialeffects on cognition in AD. Methods: A serotonergic synaptic cleft model was developed by integrating serotonin firing, release, synaptic half-life, drug/tracer properties (affinity and agonism) as inputs and5-HT4 activity as output. The serotonergic model was calibrated using bothinvivo data on free 5-HT levels in preclinical models and human imaging data. The model was further expanded to other neurontransmitter systems and incorporated into a computer-based cortical network model which implemented the physiology of 12 different membrane CNS targets. A biophysically realistic, multi-compartment model of 80 pyramidal cells and 40 interneurons was further calibrated usingdata reported for working memory tasks in healthyhumans and schizophrenia patients. Model output was the duration of the network firing activity in response to an external stimulus. Alzheimer’s disease (AD) pathology, in particular synapse and neuronal cell loss in addition to cholinergic deficits, was calibrated to align with the natural clinical disease progression. The model was used to provide insights into the effect of 5-HT4 activation on working memory and to prospectively simulate the response of PF- 04995274, a 5-HT4partial agonist, in a scopolamine-reversal trial in healthy human subjects. Results: The model output suggested a beneficial effect of 5-HT4 agonism on working memory. The model also projected no effect or an exacerbation of scopolamine impairment for low in- trinsic activity 5-HT4agonists, which was supported by the subsequent human trial outcome. The clinical prediction of the disease model strongly suggests that 5-HT4 agonists with high intrinsic activity may have a beneficial effect on cognition in AD patients.
基金This work was partly supported by the National Natural Science Foundation of China. A part of the data has been presented on a China-US Neuroscience Conference sponsored by Academia Sinica and National Academy of Science, USA, June 7-11, 1986, at Shangh
文摘A-α-CAO induces weak analgesia with very short duration in mice and is able to antagonize the analgesic effect of morphine (Mor) up to 3—4 days after a single injection. No tendency of dependence has been observed. It acts as a partial agonist on MVD with Ke value of 9×10^(-9) mol/L. Its antagonist effect remains after several washes and its agonist effect cannot be reversed by naloxone (Nx), provided the incubation time or the concentration of the agent is sufficient. On isolated GPI, A-α-CAO is a pure agonist with IC_(50) of 5.7×10^(-10) mol/L; this agonist effect cannot be removed by washing but can be reversed by Nx. On RVD and RbVD, it has antagonist effect against β-endorphine (β-end) and US0488H, which cannot be washed out easily, and the pA_2are 7.5 and 7.6 respectively. A-α-CAO also inhibits the specific binding of ~3H-etorphine (~3H-Etor) to the P_2 fraction of the mouse brain membrane with an IC_(30) of 3.2×10^(-9) mol/L. The inhibition on the high affinity binding sites of ~3H-Etor remains 95％ even after 6 washes.
文摘目的:荟萃分析方法评价5-羟色胺(5-HT)1A受体部分激动剂治疗功能性消化不良(FD)的临床疗效及安全性。方法:计算机检索PubMed、Web of Science、CNKI等数据库建库起公开发表的5-HT1A受体部分激动剂治疗FD的随机对照研究(RCT)。RevMan 5.4软件对纳入的资料荟萃分析,并进行亚组分析、分层分析,评价5-HT1A受体部分激动剂对FD的疗效及安全性。结果:纳入19项RCT,共计1575例患者(治疗组801例,对照组774例)。荟萃分析显示:治疗组总有效率高于对照组(OR=4.18,95%CI:3.05~5.73,P<0.00001),而消化道症状评分(SMD=-1.30,95%CI:-1.95~-0.64,P=0.0001)、焦虑状态评分(SMD=-1.22,95%CI:-1.79~-0.65,P<0.0001)和抑郁状态评分(SMD=-1.52,95%CI:-2.41~-0.63,P=0.0008)均低于对照组,嗜睡(OR=4.78,95%CI:1.80~12.70,P<0.05)、口干(OR=3.07,95%CI:1.31~7.19,P<0.05)发生率均高于对照组。结论:与常规或安慰剂治疗相比,联合应用5-HT1A受体部分激动剂能提高总体疗效,但嗜睡及口干发生率较高。
