GPR40受体苯丙酸类激动剂三维定量构效关系研究
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摘要
苯丙酸类化合物是G蛋白偶联受体40(GPR40)潜在的生物活性药物。本文基于比较分子力场分析法(Co MFA)和比较分子相似性指数分析法(CoMSIA),分别建立了40个已知活性的GPR40受体苯丙酸类激动剂的三维定量构效关系(3D-QSAR)模型,研究该类激动剂与生物活性之间的关系。CoMFA和CoMSIA模型的交叉验证系数(q~2)分别为0. 527和0. 500,拟合验证系数(r~2)分别为0. 901和0. 860,两个3D-QSAR模型预测值与实验值基本一致,表明模型具有良好的可信度和预测能力。根据两个3D-QSAR模型提供的立体场、静电场、疏水场、氢键供体场和氢键受体场所提供的信息提出优化该类抑制剂结构的药物设计思路,为指导设计更高活性的GPR40激动剂以及GRR40新分子激动活性的预测提供理论依据。
Phenylpropionic acid compounds are potential bioactive drugs for G protein coupled receptor 40( GPR40). Based on the comparative molecular force field analysis( CoMFA) and comparative molecular similarity index analysis( CoMSIA),the 3D-QSAR models of 40 known active GPR40 receptor phenylpropionic acid agonists were established,respectively. This experiment investigated the 3D-QSAR between this type of agonist and their biological activity. The cross-validation coefficients( q~2) of the Co MFA model and CoMSIA model are 0. 527 and 0. 500,and the fitting verification coefficients( r~2) are 0. 901 and 0. 860. The predicted values of two models are basically consistent with the experimental values,and both models have good predictive ability. Furthermore,according to the information provided by models of the stereo field,electrostatic field,hydrophobic field,hydrogen bond donor field and hydrogen bond acceptor site,the drug design ideas for optimizing the structure of the inhibitor are proposed,and provide a theoretical basis for guiding the design of higher activity GPR40 agonists and the prediction of agonistic activity of new GRR40 molecules.
Phenylpropionic acid compounds are potential bioactive drugs for G protein coupled receptor 40( GPR40). Based on the comparative molecular force field analysis( CoMFA) and comparative molecular similarity index analysis( CoMSIA),the 3D-QSAR models of 40 known active GPR40 receptor phenylpropionic acid agonists were established,respectively. This experiment investigated the 3D-QSAR between this type of agonist and their biological activity. The cross-validation coefficients( q~2) of the Co MFA model and CoMSIA model are 0. 527 and 0. 500,and the fitting verification coefficients( r~2) are 0. 901 and 0. 860. The predicted values of two models are basically consistent with the experimental values,and both models have good predictive ability. Furthermore,according to the information provided by models of the stereo field,electrostatic field,hydrophobic field,hydrogen bond donor field and hydrogen bond acceptor site,the drug design ideas for optimizing the structure of the inhibitor are proposed,and provide a theoretical basis for guiding the design of higher activity GPR40 agonists and the prediction of agonistic activity of new GRR40 molecules.
引文
[1]D D Feng,Z Q Luo,S G Roh et al.Endocrinology 2006;147(2):674~682.
[2]A P Liou,X Lu,Y Sei et al.Gastroenterology,2011,140(3):903~912.
[3]D Ma,B Tao,S Warashina et al.Neurosci.Res.,2007,58(4):394~401.
[4]A Srivastava,J Yano,Y Hirozane et al.Nature,2014,513(7516):124~127.
[5]S Mikami,S Kitamura,N Negoro et al.J.Med.Chem.,2012,55(8):3756~3776.
[6]N Negoro,S Sasaki,S Mikami et al.J.Med.Chem.,2012,55(8):3960~3974.
[7]N Negoro,S Sasaki,M Ito et al.J.Med.Chem.,2012,55(4):1538~1552.
[8]曹洪玉,吴艳华,任聪等.化学通报,2018,81(6):548~554.
[9]于柯楠,吴玲,曹洪玉.广东化工,2016,43(05):15~18.
[10]李国栋,彭发,陈兰美等.化学研究与应用,2015,27(2):113~121.
[2]A P Liou,X Lu,Y Sei et al.Gastroenterology,2011,140(3):903~912.
[3]D Ma,B Tao,S Warashina et al.Neurosci.Res.,2007,58(4):394~401.
[4]A Srivastava,J Yano,Y Hirozane et al.Nature,2014,513(7516):124~127.
[5]S Mikami,S Kitamura,N Negoro et al.J.Med.Chem.,2012,55(8):3756~3776.
[6]N Negoro,S Sasaki,S Mikami et al.J.Med.Chem.,2012,55(8):3960~3974.
[7]N Negoro,S Sasaki,M Ito et al.J.Med.Chem.,2012,55(4):1538~1552.
[8]曹洪玉,吴艳华,任聪等.化学通报,2018,81(6):548~554.
[9]于柯楠,吴玲,曹洪玉.广东化工,2016,43(05):15~18.
[10]李国栋,彭发,陈兰美等.化学研究与应用,2015,27(2):113~121.