4-羟氨基-α-吡喃酮甲酰胺类似物的3D-QSAR及分子对接研究
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摘要
采用Topomer CoMFA方法对42个4-羟氨基-α-吡喃酮甲酰胺类似物进行三维定量构效关系(3D-QSAR)分析.所得最优模型的拟合、交互验证、及外部验证的复相关系数分别为0.926、0.638、0.923,结果表明该模型具有良好的稳定性和预测能力.采用Topomer Search技术在ZINK数据库中进行虚拟筛选,筛选出2个R1基团和16个R2基团,进而设计出32个具有更高活性的新型4-羟氨基-α-吡喃酮甲酰胺类化合物.采用分子对接技术对药物与受体的作用机制进行了研究,结果显示,药物与蛋白酶的ARG47、ILE368和GLY201位点作用明显,该QSAR的研究结果可为新药合成提供理论参考.
Topomer CoMFA was adopted to study the three-dimensional quantitative structure-activity relationship(3 D-QSAR)for 42 4-hydroxyamino α-pyranone carboxamide analogues. The correlation coefficient of cross-validation, non-cross-validation and external validation are 0.926、0.638 and 0.923, respectively. The results indicated that the model obtained has both favorable estimation stability and good prediction capability. Topomer Search was used to search appropriate R groups from ZINC database, 36 new compounds with effective high activities were designed. By using molecular docking, the action mechanism of drug and acceptor was studied, and the results showed that the drug functions obviously with ARG47、ILE368 and GLY201 sites of protease. The QSAR study could provide a theoretical reference for the synthesis of new drugs.
Topomer CoMFA was adopted to study the three-dimensional quantitative structure-activity relationship(3 D-QSAR)for 42 4-hydroxyamino α-pyranone carboxamide analogues. The correlation coefficient of cross-validation, non-cross-validation and external validation are 0.926、0.638 and 0.923, respectively. The results indicated that the model obtained has both favorable estimation stability and good prediction capability. Topomer Search was used to search appropriate R groups from ZINC database, 36 new compounds with effective high activities were designed. By using molecular docking, the action mechanism of drug and acceptor was studied, and the results showed that the drug functions obviously with ARG47、ILE368 and GLY201 sites of protease. The QSAR study could provide a theoretical reference for the synthesis of new drugs.
引文
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[2] Xie W W,Meng C,Guan S M.Analysis of current status of Hepatitis C Virus NS3 antigen detection [J].Beijing Med.J.,2018,40:144 (in Chinese) [谢无畏,孟超,关素梅.丙型肝炎病毒NS3抗原检测现状分析 [J].北京医学,2018,40:144]
[3] Liang T J.Current progress in development of hepatitis C virus vaccines [J].Nat.Med.,2013,19:869.
[4] Houghton M.Prospects for prophylactic and therapeutic vaccines against the hepatitis C viruses [J].Immunol.Rev.,2011,239:99.
[5] Jin S.Antiviral treatment of chronic hepatitis C with genotype 1 HCV infection [J].J.Mod.Med.Health,2012,28:256 (in Chinese) [金生.基因1型HCV感染慢性丙型肝炎的抗病毒治疗 [J].现代医药卫生,2012,28:256]
[6] Delang L,Paeshuyse J,Vliegen I,et al.Statins potentiate the in vitro anti-hepatitis C virus activity of selective hepatitis C virus inhibitors and delay or prevent resistance development [J].Hepatology,2009,50:6.
[7] Bartels D J,Sullivan J C,Zhang E Z,et al.Hepatitis C virus variants with decreased sensitivity to direct-acting antivirals (DAAs) were rarely observed in DAA-naive patients prior to treatment [J].J.Virol.,2013,87:1544.
[8] Sarrazin C,Wedemeyer H,Cloherty G,et al.Importance of very early HCV RNA kinetics for prediction of treatment outcome of highly effective all oral direct acting antiviral combination therapy [J].J.Virol.Methods,2015,214:29.
[9] Lee S,Barron M G.A mechanism-based 3D-QSAR approach for classification and prediction of acetylcholinesterase inhibitory potency of organophosphate and carbamate analogs [J].J.Comput.Aid.Mol.Des.,2016,30:347.
[10] Tong J B,Jiang G Y,Li Y Y,et al.3D-QSAR study on antimicrobial peptides by CoMFA method [J].J.At.Mol.Phys.,2017,34:990 (in Chinese) [仝建波,江国艳,李园园,等.应用CoMFA研究抗菌肽的三维定量构效关系 [J].原子与分子物理学报,2017,34:990]
[11] Tong J B,Qin S S,Lei S,et al.3D-QSAR studies of thiazolidenebenzenesulfonamide derivatives based on Topomer CoMFA method and molecular design [J].J.At.Mol.Phys.,2018,35:925 (in Chinese) [仝建波,秦尚尚,雷珊,等.基于Topomer CoMFA的苯磺酰基亚胺噻唑衍生物的三维定量构效关系研究和分子设计[J].原子与分子物理学报,2018,35:925]
[12] Cramer R D,Patterson D E,Bunce J D.Comparative molecular field analysis(CoMFA).1.Effect of shape on binding of steroids to carrier proteins [J].J.Am.Chem.Soc.,1988,110:5959.
[13] Klebe G.Comparative molecular similarity indices analysis:CoMSIA [J].Perspect.Drug.Discovery.,1998,12:87.
[14] Ding W,Sun M,Luo S,et al.A 3D QSAR study of betulinic acid derivatives as anti-tumor agents using Topomer CoMFA:model building studies and experimental verification [J].Molecules,2013,18:10228.
[15] Joshi S D,More U A,Aminabhavi T M,et al.Two-and three-dimensional QSAR studies on a set of antimycobacterial pyrroles:CoMFA,Topomer CoMFA,and HQSAR [J].Med.Chem.Res.,2014,23:107.
[16] Konreddy A K,Toyama M,Ito W,et al.Synthesis and anti-HCV activity of 4-Hydroxyamino α-Pyranone carboxamide analogues [J].ACS.Med.Chem.Lett.,2014,5:259.
[17] Shao X,Bian X,Cai W.An improved boosting partial least squares method for near-infrared spectroscopic quantitative analysis [J].Anal.Chim.Acta.,2010,666:32.
[18] Tong J B,Li K N,Wu Y J,et al.QSAR studies of bitter tasting thresholds by 3D-HoVAIF [J].J.At.Mol.Phys.,2017,34:155 (in Chinese) [仝建波,李康楠,吴英纪,等.三维全息原子场作用矢量用于苦味二肽QSAR研究 [J].原子与分子物理学报,2017,34:155]
[19] Shao Z,Er M J,Wang N.An efficient leave-one-out cross-validation-based extreme learning machine (ELOO-ELM) With minimal user intervention [J].IEEE T.Cybernetics,2016,46:1939.
[20] Makarov D E,Plaxco K W.The topomer search model:A simple,quantitative theory of two-state protein folding kinetics [J].Protein Sci.,2010,12:17.
[21] Tong J B,Bai M,Zhao X.3D-QSAR and docking studies of HIV-1 protease inhibitors using R-group search and Surflex-dock [J].Med.Chem.Res.,2016,25:2619.
[22] Tong J B,Zhan P,Bai M,et al.Molecular modeling studies of human immunodeficiency virus type 1 protease inhibitors using three-dimensional quantitative structure-activity relationship,virtual screening,and docking simulations [J].J.Chemometr.,2016,30:523.