该文以降压靶标膜ATP敏感钾通道(ATP-sensitive potassium channel,KATP)为研究对象,构建其基于配体和基于受体结构的药效团模型,并分别筛选中药化学成分数据库(traditional Chinese medicine database,TCMD),利用分子对接评价筛选结果...该文以降压靶标膜ATP敏感钾通道(ATP-sensitive potassium channel,KATP)为研究对象,构建其基于配体和基于受体结构的药效团模型,并分别筛选中药化学成分数据库(traditional Chinese medicine database,TCMD),利用分子对接评价筛选结果,发现具有潜在KATP开放作用的中药降压活性成分。其中,基于配体的药效团模型(ligand based pharmacophore,LBP)以对人源KATP具有开放活性的48个化合物为研究对象,利用Hypogen模块进行构建,最优模型由1个氢键受体、1个氢键供体、1个疏水基团、1个芳香环和5个排除体积组成,预测训练集化合物活性相关系数为0.876 4,测试集相关系数为0.705 8,辨识有效性指数N为3.304,综合评价指数CAI为2.616;以KATP同源模建模型(PM0079770)为研究对象,构建基于受体的药效团模型(structure-based pharmacophore,SBP),最优模型具有6个氢键受体、8个氢键供体、7个疏水基团和18个排除体积,辨识有效性指数N为2.200,综合评价指数CAI为2.017。分别用2个最优模型对TCMD数据库进行筛选,对候选化合物进行Lipinski五规则及ADMET性质预测研究,LBP模型命中171个化合物,SBP模型命中178个化合物。利用分子对接技术分别对上述2组潜在中药活性成分进行评价,按照打分值由大到小的排序,分别选取对接pose个数的前3%为潜在活性化合物。得到由LBP模型虚拟筛选得到的10个化合物、由SBP模型虚拟筛选得到的2个化合物,共12个具有潜在KATP开放活性的中药成分。该研究为发现新的KATP开放剂提供了思路。展开更多
Objective To investigate the effectiveness of pinacidil,an opener of ATP-sensitive K+ channels,in protecting the myocardium of immature rabbit hearts from ischemic reperfusion injury.Methods Rabbit hearts underwent 30...Objective To investigate the effectiveness of pinacidil,an opener of ATP-sensitive K+ channels,in protecting the myocardium of immature rabbit hearts from ischemic reperfusion injury.Methods Rabbit hearts underwent 30 min of global normothermic ischemia followed by 30 min of reperfusion on the modified Langendorff apparatus.Fifty-two isolated hearts of 3 - 4 week-old immature rabbits were divided into 4 groups randomly.During ischemia,3 different cardioplegic solutions were administered intermittently by infusion every 15 min(20-25 mi each time in all groups).Group 1:control group(n = 13);group 2:Krebs-Henseleit(K-H)solution with potassium(16 mmol/L)(n = 1:3);group 3:K-H solution with potassium(16 mmol/L)and pinacidil(50 μmol/L)(n = 13);group 4:K-H solution with potassium(16 mmol/L),pinacidil(50 μmol/L)and glibenclamide(10 μmol/L)(n = 13).The pre-ischemic and post-ischemic myocardial functions were assessed by the percentage recovery of the left ventricular developed pressure(LVDP);the left ventricular end-diastolic pressure(LVEDP);both the Positive peak and negative peaks of the first derivative of the left ventricular pressures(± dp/dtmax);coronary flow;the level of creatine kinase(CK),lactic dehydrogenase(LDH)and aspartate transcarbamoylase(AST)in coronary sinus venous effluent;and by myocardial ultrastructural changes.Results Before myocardial ischemia,there were no significant differences among the four groups in any of the parameters mentioned above.Post-ischemic recovery of LVDP,LVEDP,± dp/dtmax,coronary flow,the level of CK,LDH and AST,and myocardial ultrastructural changes were better in group 3 than those in the three other groups.Conclusions As a new and effective composition,pinacidil can significantly improve myocardial protection from cardioplegia for immature rabbit hearts.展开更多
文摘该文以降压靶标膜ATP敏感钾通道(ATP-sensitive potassium channel,KATP)为研究对象,构建其基于配体和基于受体结构的药效团模型,并分别筛选中药化学成分数据库(traditional Chinese medicine database,TCMD),利用分子对接评价筛选结果,发现具有潜在KATP开放作用的中药降压活性成分。其中,基于配体的药效团模型(ligand based pharmacophore,LBP)以对人源KATP具有开放活性的48个化合物为研究对象,利用Hypogen模块进行构建,最优模型由1个氢键受体、1个氢键供体、1个疏水基团、1个芳香环和5个排除体积组成,预测训练集化合物活性相关系数为0.876 4,测试集相关系数为0.705 8,辨识有效性指数N为3.304,综合评价指数CAI为2.616;以KATP同源模建模型(PM0079770)为研究对象,构建基于受体的药效团模型(structure-based pharmacophore,SBP),最优模型具有6个氢键受体、8个氢键供体、7个疏水基团和18个排除体积,辨识有效性指数N为2.200,综合评价指数CAI为2.017。分别用2个最优模型对TCMD数据库进行筛选,对候选化合物进行Lipinski五规则及ADMET性质预测研究,LBP模型命中171个化合物,SBP模型命中178个化合物。利用分子对接技术分别对上述2组潜在中药活性成分进行评价,按照打分值由大到小的排序,分别选取对接pose个数的前3%为潜在活性化合物。得到由LBP模型虚拟筛选得到的10个化合物、由SBP模型虚拟筛选得到的2个化合物,共12个具有潜在KATP开放活性的中药成分。该研究为发现新的KATP开放剂提供了思路。
基金ThisworkwassupportedbyagrantfromtheScienceAssociationofZhejiangProvince (No 97110 3 10 2 )
文摘Objective To investigate the effectiveness of pinacidil,an opener of ATP-sensitive K+ channels,in protecting the myocardium of immature rabbit hearts from ischemic reperfusion injury.Methods Rabbit hearts underwent 30 min of global normothermic ischemia followed by 30 min of reperfusion on the modified Langendorff apparatus.Fifty-two isolated hearts of 3 - 4 week-old immature rabbits were divided into 4 groups randomly.During ischemia,3 different cardioplegic solutions were administered intermittently by infusion every 15 min(20-25 mi each time in all groups).Group 1:control group(n = 13);group 2:Krebs-Henseleit(K-H)solution with potassium(16 mmol/L)(n = 1:3);group 3:K-H solution with potassium(16 mmol/L)and pinacidil(50 μmol/L)(n = 13);group 4:K-H solution with potassium(16 mmol/L),pinacidil(50 μmol/L)and glibenclamide(10 μmol/L)(n = 13).The pre-ischemic and post-ischemic myocardial functions were assessed by the percentage recovery of the left ventricular developed pressure(LVDP);the left ventricular end-diastolic pressure(LVEDP);both the Positive peak and negative peaks of the first derivative of the left ventricular pressures(± dp/dtmax);coronary flow;the level of creatine kinase(CK),lactic dehydrogenase(LDH)and aspartate transcarbamoylase(AST)in coronary sinus venous effluent;and by myocardial ultrastructural changes.Results Before myocardial ischemia,there were no significant differences among the four groups in any of the parameters mentioned above.Post-ischemic recovery of LVDP,LVEDP,± dp/dtmax,coronary flow,the level of CK,LDH and AST,and myocardial ultrastructural changes were better in group 3 than those in the three other groups.Conclusions As a new and effective composition,pinacidil can significantly improve myocardial protection from cardioplegia for immature rabbit hearts.
