一类新型6-烷氨基-2-烷硫基嘌呤核苷衍生物抗血小板凝集的3D-QSAR研究
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摘要
通过自组织分子场分析(SOMFA)方法,对20个具有测试活性的2-烷硫基-6-烷氨基嘌呤核苷衍生物进行三维定量构效关系(3D-QSAR)研究,得到预测能力最佳的SOMFA模型,其中交叉验证系数r2cv=0.801,非交叉验证系数r2=0.807,统计方差比F=75.281,标准方差s=0.130。同时,通过对该模型的立体场和静电场三维网格图进行分析,能够较清晰直观地为设计新型的高活性抗血小板药物分子提供理论指导。
Twenty 6-alkylamino-2-alkylthio adenosine derivatives with tested antiplatelet aggregation activity were subjected to a self-organized molecular field analysis( SOMFA),and a three-dimensional-quantitative structure-activity relationship( 3D-QSAR) analysis. By using the multiple regression method,a best SOMFA model with good predictive functionality was generated with r2cv= 0. 801,r2= 0. 807,F = 75. 281,and s = 0. 130. Analyzing the 3D electrostatic and shape potential master grid of this model provides a useful clear and intuitive theoretical guide for designing new antiplatelet aggregation inhibitors.
Twenty 6-alkylamino-2-alkylthio adenosine derivatives with tested antiplatelet aggregation activity were subjected to a self-organized molecular field analysis( SOMFA),and a three-dimensional-quantitative structure-activity relationship( 3D-QSAR) analysis. By using the multiple regression method,a best SOMFA model with good predictive functionality was generated with r2cv= 0. 801,r2= 0. 807,F = 75. 281,and s = 0. 130. Analyzing the 3D electrostatic and shape potential master grid of this model provides a useful clear and intuitive theoretical guide for designing new antiplatelet aggregation inhibitors.
引文
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[3]Schr9r K.The basic pharmacology of ticlopidine and clopidogrel[J].Platelets,1993,4(5):252-261.
[4]Husted S,van Giezen J J J.Ticagrelor:the first reversibly binding oral P2Y12receptor antagonist[J].Cardiovascular Therapeutics,2009,27(4):259-274.
[5]Borea P A,Varani K,Vincenzi F,et al.The A3adenosine receptor:history and perspectives[J].Pharmacological Reviews,2015,67(1):74-102.
[6]Mc Guigan C,Serpi M,Slusarczyk M,et al.Anti-flavivirus activity of different tritylated pyrimidine and purine nucleoside analogues[J].Chemistry Open,2016,5:227-235.
[7]Meneghesso S,Vanderlinden E,Brancale A,et al.Synthesis and biological evaluation of purine 2’-fluoro-2’-deoxyriboside protides as anti-influenza virus agents[J].Chem Med Chem,2013,8(3):415-425.
[8]Halbfinger E,Major D T,Ritzmann M,et al.Molecular recognition of modified adenine nucleotides by the P2Y1-receptor.1.A synthetic,biochemical,and NMR approach[J].Journal of Medicinal Chemistry,1999,42(26):5325-5337.
[9]Robinson D D,Winn P J,Lyne P D,et al.Self-organizing molecular field analysis:a tool for structure-activity studies[J].Journal of Medicinal Chemistry,1999,42(4):573-583.
[10]Martin Y C.3D QSAR:current state,scope,and limitations[J].Perspectives in Drug Discovery and Design,1998,12/13/14:3-23.
[11]Smith P A,Sorich M J,Mc Kinnon R A,et al.Pharmacophore and quantitative structure-activity relationship modeling:complementary approaches for the rationalization and prediction of UDP-glucuronosyltransferase 1A4substrate selectivity[J].Journal of Medicinal Chemistry,2003,46(9):1617-1626.
[12]Tuppurainen K,Viisas M,PerkylM,et al.Ligand intramolecular motions in ligand-protein interaction:ALPHA,a novel dynamic descriptor and a QSAR study with extended steroid benchmark dataset[J].Journal of Computer-Aided Molecular Design,2004,18(3):175-187.
[13]Klocker J,Wailzer Bettina,Buchbauer G,et al.Aroma quality differentiation of pyrazine derivatives using self-organizing molecular field analysis and artificial neural network[J].Journal of Agricultural and Food Chemistry,2002,50(14):4069-4075.
[14]Korhonen S P,Tuppurainen K,Laatikainen R,et al.Improving the performance of SOMFA by use of standard multivariate methods[J].SAR and QSAR in Environmental Research,2005,16(6):567-579.
[15]Liu G C,Xu J X,Chen N,et al.Synthesis of N6-alkyl(aryl)-2-alkyl(aryl)thioadenosines as antiplatelet agents[J].European Journal of Medicinal Chemistry,2012,53:114-123.
[16]Li S L,Zheng Y.Self-organizing molecular field analysis on a new series of COX-2 selective inhibitors:1,5-diarylimidazoles[J].International Journal of Molecular Sciences,2006,7(7):220-229.
[17]Li S L,He M Y,Du H G.3D-QSAR studies on a series of dihydroorotate dehydrogenase inhibitors:analogues of the active metabolite of leflunomide[J].International Journal of Molecular Sciences,2011,12(5):2982-2993.
[18]Li S L,Zhang R T,Du H G.3D-QSAR study on a series of VEGFR-2 kinase inhibitors:3-pyrrole substituted indolin-2-ones compounds[J].Journal of Chemistry,2013,49:374804.
[19]邓聪迩.6-烷氨基/烷氧基-2-丙硫基-8-氮杂嘌呤核苷的合成及抗血小板凝聚活性评价[D].北京:北京化工大学,2013.Deng C E.Synthesis of 6-alkylamino/alkoxy-2-propylthio-8-azapurine and evaluation of antiplatelet agglutination activity[D].Beijing:Beijing University of Chemical Technology,2013.(in Chinese)
[20]Douglass J G,de Camp J B,Fulcher E H,et al.Adenosine analogues as inhibitors of P2Y12receptor mediated platelet aggregation[J].Bioorganic&Medicinal Chemistry Letters,2008,18(6):2167-2171.