吡唑啉嘧啶类IL-2诱导T细胞激酶抑制剂的三维定量构效关系研究和虚拟筛选
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摘要
为获取结构新颖、高活性的Itk抑制剂,采用Co MFA和Co MSIA两种方法对39个吡唑啉嘧啶类Itk抑制剂进行三维定量构效关系研究,新建模型的交叉验证系数分别为q2=0.771和q2=0.759,拟合验证系数分别为r2=0.948和r2=0.913,结果表明模型具有良好的可信度和预测能力。运用药效团模型虚拟筛选、分子对接和3D-QSAR模型的分子活性预测等方法进行虚拟筛选,最终获得7个高活性的新抑制剂化合物。Surflexdock分析显示新抑制剂与Itk靶点有较强的的氢键作用。各研究结果表明,此定量构效关系研究和虚拟筛选方法可有效地用于吡唑啉嘧啶类Itk抑制剂的分子设计,为Itk靶向药物的研发及合成提供参考。
In order to obtain novel and highly active Itk inhibitors,the three-dimensional quantitative structure-activity relationship of 39 Itk inhibitors of pyrazolopyrimidine was studied by two methods of Co MFA and Co MSIA.The cross validation coefficients of the new models are q2= 0. 771 and q2= 0. 759 respectively,and the coefficients of determination are r2= 0. 948 and r2= 0. 913 respectively.The results of 3 D-QSAR models show that the models have good reliability and prediction ability.Virtual screening of pharmacophore model,molecular docking and molecular activity prediction of 3 D-QSAR model were applied to virtual screening,and seven new highly active inhibitors were obtained. Surflex-dock analysis showedsthat the new inhibitorshashave strong hydrogen bond with Itk target.The research results show that this quantitative structure-activity relationship study and virtual screening method can be effectively used in the molecular design of Itk inhibitors of pyrazolopyrimidine and provide a reference for the development and synthesis of Itk targeted drugs.
In order to obtain novel and highly active Itk inhibitors,the three-dimensional quantitative structure-activity relationship of 39 Itk inhibitors of pyrazolopyrimidine was studied by two methods of Co MFA and Co MSIA.The cross validation coefficients of the new models are q2= 0. 771 and q2= 0. 759 respectively,and the coefficients of determination are r2= 0. 948 and r2= 0. 913 respectively.The results of 3 D-QSAR models show that the models have good reliability and prediction ability.Virtual screening of pharmacophore model,molecular docking and molecular activity prediction of 3 D-QSAR model were applied to virtual screening,and seven new highly active inhibitors were obtained. Surflex-dock analysis showedsthat the new inhibitorshashave strong hydrogen bond with Itk target.The research results show that this quantitative structure-activity relationship study and virtual screening method can be effectively used in the molecular design of Itk inhibitors of pyrazolopyrimidine and provide a reference for the development and synthesis of Itk targeted drugs.
引文
[1]Xu W D,Su L C,Xie Q B,et al.Interleukin-2-inducible Tcell kinase expression and relation to disease severity in systemic lupus erythematosus[J].Clin Chim Acta,2016,463:11-17.
[2]Huang W S.Role(s)of IL-2 inducible T cell kinase and Bruton's tyrosine kinase in mast cell response to lipopolysaccharide[J].Genomics Data,2016,8:18-20.
[3]Gillian M,Schiralli L,Hisashi A,et al.Interleukin 2-inducible T cell kinase(ITK)facilitates efficient egress of HIV-1 by coordinating Gag distribution and actin organization[J].Virology,2013,436(1):235-243.
[4]Liang P L,Chang S T,Ye H T,et al.Angioimmunoblastic T-cell lymphoma in taiwan showed a frequent gain of ITK gene[J].Pathology,2014,46(2):98.
[5]He F,Yao H L,Xiao Z H,et al.Inhibition of IL-2 inducible T-cell kinase alleviates T-cell activation and murine myocardial inflammation associated with CVB3 infection[J].Mol Immunol,2014,59(1):30-38.
[6]Cho S H,Conley J,Shin H M,et al.94 A covalent inhibitor of ITK and RLK inhibits Th1 and Th17 cell differentiation and prevents disease manifestation in an adoptive transfer model of colitis[J].Gastroenterology,2015,148(4):27.
[7]Herdemann M,Weber A,Jonveaux J,et al.Optimisation of ITK inhibitors through successive iterative design cycles[J].Bioorg Med Chem Lett,2011,21(6):1852-1856.
[8]何峰,姚海兰,肖宗慧,等.Itk蛋白在人PBMC增殖和细胞因子产生中的作用研究[J].现代免疫学,2010,30(1):5-8.
[9]Mukherjee S,Rigaud S,Sauer K,et al.Competing negative and positive feedback generate specific T cell responses by tuning duration and amplitude of Itk activation[J].Biophysical Journal,2011,100(3):178.
[10]Pastor R M,Burch J D,Magnuson S,et al.Discovery and optimization of indazoles as potent and selective interleukin-2 inducible T cell kinase(ITK)inhibitors[J].Bioorg Med Chem Lett,2014,24(11):2448-2452.
[11]Herdemann M,Heit I,Bosch F U,et al.Identification of potent ITK inhibitors through focused compound library design including structural information[J].Bioorg Med Chem Lett,2016,20(23):6998-7003.
[12]Moriaty K J,Winters M,Qiao L,et al.Itk kinase inhibitors:Initial efforts to improve the metabolical stability and the cell activity of the benzimidazole lead[J].Bioorg Med Chem Lett,2008,18(20):5537-5540.
[13]Meng L,Huayun F,Cheng W,et al.3D-QSAR-aided design,synthesis,in vitro and in vivo evaluation of dipeptidyl boronic acid proteasome inhibitors and mechanism studies[J].Bioorgan Med Chem,2016,24:2576-2588.
[14]Paresh P,Chetan C,Manjunath G,et al.3D QSAR study of 4H-Chromen-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives as potential anti-mycobacterial agents[J].Med Chem Res,2014,23:2955-2963.
[15]Akamatsu M.Current state and perspectives of 3D-QSAR[J].Curr Top Med Chem,2002,2(12),1381-1394.
[16]Almerico AM,Tutone M,Lauria A.Receptor-guided 3DQSAR approach for the discovery of C-kit tyrosine kinase inhibitors[J].J Mol Model,2012,18(7):2885-2895.
[17]Christoph W Z,Brian S G,Li Xing,et al.Covalent inhibitors of interleukin-2 inducible T cell kinase(Itk)with nanomolar potency in a whole-blood assay[J].J Med Chem,2012,55:10047-10063.
[18]王文鹃,相玉红,宋佳,等.基于他克林的乙酰胆碱酯酶抑制剂的3D-QSAR研究及虚拟筛选[J].化学研究与应用,2014,26(2):241-249.
[19]Sukriti G,Sonam B,Jaspreet K D,et al.Group-based QSAR and molecular dynamics mechanistic analysis revealing the mode of action of novel piperidinone derived protein–protein inhibitors of p53-MDM2[J].J Mol Graph Model,2014,51:64-72.
[20]Yan X Q,Wang Z C,Li Zhen,et al.Sulfonamide derivatives containing dihydropyrazole moieties selectively and potently inhibit MMP-2/MMP-9:Design,synthesis,inhibitory activity and 3D-QSAR analysis[J].Bioorgan Med Chem,2015,25(20):4664-4671.
[21]Sangeethaa K,Sasikala R P,Meena K S.Pharmacophore modeling,virtual screening and molecular docking of ATPase inhibitors of HSP70[J].Comput Biol Chem,2017,70:164-174.
[22]张贝娜,武涛,宰小丽,等.吡啶类葡萄糖激酶激动剂的三维定量构效关系分析[J].化学研究与应用,2017,29(4):492-498.
[23]Asati V,Bharti S K,Budhwani A K.3D-QSAR and virtual screening studies of thiazolidine-2,4-dione analogs:Validation of experimental inhibitory potencies towards PIM-1kinase[J].J Mol Struct,2017,1133:278-293.
[2]Huang W S.Role(s)of IL-2 inducible T cell kinase and Bruton's tyrosine kinase in mast cell response to lipopolysaccharide[J].Genomics Data,2016,8:18-20.
[3]Gillian M,Schiralli L,Hisashi A,et al.Interleukin 2-inducible T cell kinase(ITK)facilitates efficient egress of HIV-1 by coordinating Gag distribution and actin organization[J].Virology,2013,436(1):235-243.
[4]Liang P L,Chang S T,Ye H T,et al.Angioimmunoblastic T-cell lymphoma in taiwan showed a frequent gain of ITK gene[J].Pathology,2014,46(2):98.
[5]He F,Yao H L,Xiao Z H,et al.Inhibition of IL-2 inducible T-cell kinase alleviates T-cell activation and murine myocardial inflammation associated with CVB3 infection[J].Mol Immunol,2014,59(1):30-38.
[6]Cho S H,Conley J,Shin H M,et al.94 A covalent inhibitor of ITK and RLK inhibits Th1 and Th17 cell differentiation and prevents disease manifestation in an adoptive transfer model of colitis[J].Gastroenterology,2015,148(4):27.
[7]Herdemann M,Weber A,Jonveaux J,et al.Optimisation of ITK inhibitors through successive iterative design cycles[J].Bioorg Med Chem Lett,2011,21(6):1852-1856.
[8]何峰,姚海兰,肖宗慧,等.Itk蛋白在人PBMC增殖和细胞因子产生中的作用研究[J].现代免疫学,2010,30(1):5-8.
[9]Mukherjee S,Rigaud S,Sauer K,et al.Competing negative and positive feedback generate specific T cell responses by tuning duration and amplitude of Itk activation[J].Biophysical Journal,2011,100(3):178.
[10]Pastor R M,Burch J D,Magnuson S,et al.Discovery and optimization of indazoles as potent and selective interleukin-2 inducible T cell kinase(ITK)inhibitors[J].Bioorg Med Chem Lett,2014,24(11):2448-2452.
[11]Herdemann M,Heit I,Bosch F U,et al.Identification of potent ITK inhibitors through focused compound library design including structural information[J].Bioorg Med Chem Lett,2016,20(23):6998-7003.
[12]Moriaty K J,Winters M,Qiao L,et al.Itk kinase inhibitors:Initial efforts to improve the metabolical stability and the cell activity of the benzimidazole lead[J].Bioorg Med Chem Lett,2008,18(20):5537-5540.
[13]Meng L,Huayun F,Cheng W,et al.3D-QSAR-aided design,synthesis,in vitro and in vivo evaluation of dipeptidyl boronic acid proteasome inhibitors and mechanism studies[J].Bioorgan Med Chem,2016,24:2576-2588.
[14]Paresh P,Chetan C,Manjunath G,et al.3D QSAR study of 4H-Chromen-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives as potential anti-mycobacterial agents[J].Med Chem Res,2014,23:2955-2963.
[15]Akamatsu M.Current state and perspectives of 3D-QSAR[J].Curr Top Med Chem,2002,2(12),1381-1394.
[16]Almerico AM,Tutone M,Lauria A.Receptor-guided 3DQSAR approach for the discovery of C-kit tyrosine kinase inhibitors[J].J Mol Model,2012,18(7):2885-2895.
[17]Christoph W Z,Brian S G,Li Xing,et al.Covalent inhibitors of interleukin-2 inducible T cell kinase(Itk)with nanomolar potency in a whole-blood assay[J].J Med Chem,2012,55:10047-10063.
[18]王文鹃,相玉红,宋佳,等.基于他克林的乙酰胆碱酯酶抑制剂的3D-QSAR研究及虚拟筛选[J].化学研究与应用,2014,26(2):241-249.
[19]Sukriti G,Sonam B,Jaspreet K D,et al.Group-based QSAR and molecular dynamics mechanistic analysis revealing the mode of action of novel piperidinone derived protein–protein inhibitors of p53-MDM2[J].J Mol Graph Model,2014,51:64-72.
[20]Yan X Q,Wang Z C,Li Zhen,et al.Sulfonamide derivatives containing dihydropyrazole moieties selectively and potently inhibit MMP-2/MMP-9:Design,synthesis,inhibitory activity and 3D-QSAR analysis[J].Bioorgan Med Chem,2015,25(20):4664-4671.
[21]Sangeethaa K,Sasikala R P,Meena K S.Pharmacophore modeling,virtual screening and molecular docking of ATPase inhibitors of HSP70[J].Comput Biol Chem,2017,70:164-174.
[22]张贝娜,武涛,宰小丽,等.吡啶类葡萄糖激酶激动剂的三维定量构效关系分析[J].化学研究与应用,2017,29(4):492-498.
[23]Asati V,Bharti S K,Budhwani A K.3D-QSAR and virtual screening studies of thiazolidine-2,4-dione analogs:Validation of experimental inhibitory potencies towards PIM-1kinase[J].J Mol Struct,2017,1133:278-293.