新型腺嘌呤类化合物的抗血小板凝集3D-QSAR研究
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摘要
血小板凝集导致的血栓类心血管疾病正严重威胁着人类健康,故而抵抗血小板凝集对血栓类心血管疾病的治疗至关重要。嘌呤衍生物是具有抗血小板凝集活性的重要分子,研究嘌呤结构与抗凝效果之间的关系,对治疗血栓类疾病药物的研发具有重要指导意义。本文采用自组织分子场(SOMFA)对29个新型腺嘌呤化合物结构与抗凝活性之间的关系进行3D-QSAR分析,建立最佳SOMFA模型,交叉验证系数r~2可达0.87,非交叉验证系数r_(cv)~2可达0.83,统计方差比F值为183.41,标准方差s仅为0.05,表明该模型有较好的预测能力。测试集的r~2_(pred)为0.886,表明该模型对外部化合物的药物活性具有较为可靠的预测能力。同时,立体场和静电场的三维网格图显示了取代基空间体积及电荷分布规律对活性的影响,为下一步预测、设计及合成活性更高的抗凝集嘌呤分子提供理论指导。
Cardiovascular disease caused by platelet aggregation is a serious threat to human health, so antiplatelet aggregation has great significance to treat the disease. Since, purine derivatives are important molecules with antiplatelet aggregation activity, it is very essential to study the relationship between purine structure and antiplatelet aggregation effect, which could help us to find antithrombotic drugs. In this paper, the 3 D-QSAR analysis among twenty nine adenine compounds was carried out to find the relationship between purine structure and antiplatelet effect through self-organized molecular field analysis(SOMFA). The optimal model was established, and cross-validation coefficient r~2 can reach up to 0.87, the non-cross-validation coefficient r_(cv)~2 can reach to 0.83, the statistical variance ratio is 183.41, and the standard variance is only 0.05,which show the model has enough ability to predict the antiplatelet aggregation effect of purine derivatives. The r~2 pred of the test set was 0.886, which indicates that the model has a reliable predictive performance for the activities of external compounds. Meanwhile, the effect of the volume and charge distribution was shown by 3 D grid of stereoscopic field and static electric field, providing theoretical guidance for predicting, designing,and synthesizing purine derivatives with more high antiplatelet activity.
Cardiovascular disease caused by platelet aggregation is a serious threat to human health, so antiplatelet aggregation has great significance to treat the disease. Since, purine derivatives are important molecules with antiplatelet aggregation activity, it is very essential to study the relationship between purine structure and antiplatelet aggregation effect, which could help us to find antithrombotic drugs. In this paper, the 3 D-QSAR analysis among twenty nine adenine compounds was carried out to find the relationship between purine structure and antiplatelet effect through self-organized molecular field analysis(SOMFA). The optimal model was established, and cross-validation coefficient r~2 can reach up to 0.87, the non-cross-validation coefficient r_(cv)~2 can reach to 0.83, the statistical variance ratio is 183.41, and the standard variance is only 0.05,which show the model has enough ability to predict the antiplatelet aggregation effect of purine derivatives. The r~2 pred of the test set was 0.886, which indicates that the model has a reliable predictive performance for the activities of external compounds. Meanwhile, the effect of the volume and charge distribution was shown by 3 D grid of stereoscopic field and static electric field, providing theoretical guidance for predicting, designing,and synthesizing purine derivatives with more high antiplatelet activity.
引文
1 Douglass J G,EMILEE B deC,Fulcher E H,Jones W,Mahanty S,Morgan A,Smirnov D,Boyer J L,Watson P S.Adenosine analogues as inhibitors of P2Y12receptor mediated platelet aggregation[J].Bioorganic&Medicinal Chemistry Letters,2008,18(6):167-2171.
2 Bonello L,Laine M,Thuny F,Paganelli F,Lemesle G,Roch A,Kerbaul F,Dignat-George F,Berbis J,Frere C.Platelet reactivity in patients receiving a maintenance dose of P2Y12-ADP receptor antagonists undergoing elective percutaneous coronary intervention[J].International Journal of Cardiology,2016,216:190-193.
3 Cristalli G,Volpini R,Vittori S,Camaioni E,Monopoli A,Conti A,Dionisotti S,Zocchi C,Ongini E.2-Alkynyl Derivatives of Adenosine-5'-N-ethyluronamide:Selective A2 Adenosine Receptor Agonists with Potent Inhibitory Activity on Platelet Aggregation[J].Journal of Medicinal Chemistry,1994,37(11):720-1726.
4 Mathieu R,Baurand A,Schmitt M,Gachet C,Bourguignon J J.Synthesis and biological activity of 2-alkylated deoxyadenosine bisphosphate derivatives as P2Y1 receptor antagonists[J].Bioorganic&Medicinal Chemistry,2004,12(7):1769-1779.
5 Cristalli G,Podda G M,Costanzi S,Lambertucci C,Lecchi A,Vittori S,Volpini R,Zighetti M,Cattaneo M.Effects of 5'-phosphate derivatives of 2-hexynyl adenosine and 2-phenylethynyl adenosine on responses of human platelets mediated by P2Yreceptors[J].Journal of Medicinal Chemistry,2005,48(8):2763-2766.
6 Ingall A H,Dixon J,Bailey A,Coombs M E,Cox D,Mc Inally J I,Hunt S F,Kindon N D,Teobald B J,Willis P A,Humphries R G,Leff P,Clegg J A,Smith J A,Tomlinson W.Antagonists of the Platelet P2T Receptor:?A Novel Approach to Antithrombotic Therapy[J].Journal of Medicinal Chemistry,1999,42(2):213-220.
7 Springthorpe B,Bailey A,Barton P,Birkinshaw T N,Bonnert R V,Brown R C,Chapman D,Dixon J,Guile S D,Humphries R G,Hunt S F,Ince F,Ingall A H,Kirk I P,Leeson P D,Leff P,Lewis R J,Martin B P,Mc Ginnity D F,Mortimore M P,Paine S W,Pairaudeau G,Patel A,Rigby A J,Riley R J,Teobald B J,Tomlinson W,Webborn P J,Willis P A.From ATP to AZD6140:the discovery of an orally active reversible P2Y12receptor antagonist for the prevention of thrombosis[J].Bioorganic&Medicinal Chemistry Letters,2007,17(21):6013-6018.
8 Zhang H,Liu J,Zhang L,Kong L,Yao H,Sun H.Synthesis and biological evaluation of ticagrelor derivatives as novel antiplatelet agents[J].Bioorganic&Medicinal Chemistry Letters,2012,22(11):3598-3602.
9 Tu W,Fan J,Zhang H,Xu G,Liu Z,Qu J,Yang F,Zhang L,Luan T,Yuan J,Gong A,Feng J,Sun P,Dong Q.Synthesis and biological evaluation of cyclopentyl-triazolol-pyrimidine(CPTP)based P2Y12,antagonists[J].Bioorganic&Medicinal Chemistry Letters,2014,24(1):141-146.
10 Yao G,Su G,Li K,Li B,Dong H.Comparative study of Ticagrelor and Clopidogrel in Therapeutic Effect of Acute Myocardial Infarction Patients Undergoing Percutaneous Coronary Intervention[J].Saudi Journal of Biological Sciences,2017,24(8):818-1820.
11 Zhang S,Hu L,Du H,Guo Y,Zhang Y,Niu H,Jin J,Zhang J,Liu J,Zhang X,Kunapuli S P,Ding Z.BF0801,a novel adenine derivative,inhibits platelet activation via phosphodiesterase inhibition and P2Y12 antagonism[J].Thrombosis&Haemostasis,2010,104(4):845-857.
12 Hu L,Fan Z,Du H,Ni R,Zhang S,Yin K,Ye J,Zhang Y,Wei X,Zhang X,Gross P L,Kunapuli S P,Ding Z.BF061,a novel antiplatelet and antithrombotic agent targeting P2Y??receptor and phosphodiesterase[J].Thrombosis&Haemostasis,2011,106(6):1203-1214.
13 Pan C,Wei X,Ye J,Liu G,Zhang S,Zhang Y,Du H,Ding Z.BF066,a novel dual target antiplatelet agent without significant bleeding[J].Plos One,2012,7(7):e40451.
15 Tuppurainen K,Viisas M,Per?kyl?M,Laatikainen R.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.
16 Verma J,Khedkar V M,Coutinho E C.3D-QSAR in drug design--a review[J].Current Topics in Medicinal Chemistry,2010,10(1):95-115.
18 S Tan,T Wang,H Wang,F Xu.Structure based virtual screening by distributed computing[J].Computers&Applied Chemistry,2015,32(9):1025-1030.
20 Patel H,Noolvi M,Sharma P,Jaiswal V,Bansal S,Lohan S,Kumar S,Abbot V,Dhiman S,Bhardwaj V.Quantitative structure-activity relationship(QSAR)studies as strategic approach in drug discovery[J].Medicinal Chemistry Research,2014,23(12):4991-5007.
21 VM Shahani,P Yue,S Haftchenary,W Zhao,J LLukkarila,X Zhang,D Ball,C Nona,P T Gunning,JTurkson.Identification of purine-scaffold smallmolecule inhibitors of stat3 activation by QSARStudies[J].ACS Medicinal Chemistry Letters,2010,2(1):79-84.
23 Robinson D D,Winn P J,Lyne P D,et al.Selforganizing molecular field analysis:a tool for structureactivity studies[J].Journal of Medicinal Chemistry,1999,42(4):573-583.
24 Ojha P K,Mitra I,Das R N,et al.Further exploring r m2,metrics for validation of QSPR models[J].Chemometrics&Intelligent Laboratory Systems,2011,107(1):194-205.
25 Liu G,Xu J,Chen N,Zhang S,Ding Z,Du H.Synthesis of-alkyl(aryl)-2-alkyl(aryl)thioadenosines as antiplatelet agents[J].European Journal of Medicinal Chemistry,2012,53(19):114-123.
14李顺来,陆成虎,杜洪光.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[J].北京化工大学学报(自然科学版),2017,44(04):8-13.
17文晓荣,王娟,安春红,舒茂,林治华.噻唑类Fascin蛋白抑制剂的3D-QSAR研究[J].计算机与应用化学,2016,33(8):886-890.
19李秀艳,郑艳,李顺来,杜洪光.新型二芳基取代-1,2,4-三唑类化合物的抗炎构效关系和分子对接研究[J].计算机与应用化学,2008,25(5):603-606.
22何琦文.9-取代-6-烷氨基-2-烷硫基嘌呤化合物的合成及抗血小板凝集活性[D].北京化工大学,2012.
26何琦文,杜洪光.9-乙酰氧基乙基-6-烷氨基-2-烷硫基嘌呤的合成及抗血小板凝集活性评估[J].有机化学,2012,32(09):1678-1683.
27汪韬,杜洪光.9-(2-羟基乙基)-6-烷氨基-8-甲氧基-2-烷硫基嘌呤的合成及其抗血小板凝集活性[J].有机化学,2013,33(08):1720-1727.
2 Bonello L,Laine M,Thuny F,Paganelli F,Lemesle G,Roch A,Kerbaul F,Dignat-George F,Berbis J,Frere C.Platelet reactivity in patients receiving a maintenance dose of P2Y12-ADP receptor antagonists undergoing elective percutaneous coronary intervention[J].International Journal of Cardiology,2016,216:190-193.
3 Cristalli G,Volpini R,Vittori S,Camaioni E,Monopoli A,Conti A,Dionisotti S,Zocchi C,Ongini E.2-Alkynyl Derivatives of Adenosine-5'-N-ethyluronamide:Selective A2 Adenosine Receptor Agonists with Potent Inhibitory Activity on Platelet Aggregation[J].Journal of Medicinal Chemistry,1994,37(11):720-1726.
4 Mathieu R,Baurand A,Schmitt M,Gachet C,Bourguignon J J.Synthesis and biological activity of 2-alkylated deoxyadenosine bisphosphate derivatives as P2Y1 receptor antagonists[J].Bioorganic&Medicinal Chemistry,2004,12(7):1769-1779.
5 Cristalli G,Podda G M,Costanzi S,Lambertucci C,Lecchi A,Vittori S,Volpini R,Zighetti M,Cattaneo M.Effects of 5'-phosphate derivatives of 2-hexynyl adenosine and 2-phenylethynyl adenosine on responses of human platelets mediated by P2Yreceptors[J].Journal of Medicinal Chemistry,2005,48(8):2763-2766.
6 Ingall A H,Dixon J,Bailey A,Coombs M E,Cox D,Mc Inally J I,Hunt S F,Kindon N D,Teobald B J,Willis P A,Humphries R G,Leff P,Clegg J A,Smith J A,Tomlinson W.Antagonists of the Platelet P2T Receptor:?A Novel Approach to Antithrombotic Therapy[J].Journal of Medicinal Chemistry,1999,42(2):213-220.
7 Springthorpe B,Bailey A,Barton P,Birkinshaw T N,Bonnert R V,Brown R C,Chapman D,Dixon J,Guile S D,Humphries R G,Hunt S F,Ince F,Ingall A H,Kirk I P,Leeson P D,Leff P,Lewis R J,Martin B P,Mc Ginnity D F,Mortimore M P,Paine S W,Pairaudeau G,Patel A,Rigby A J,Riley R J,Teobald B J,Tomlinson W,Webborn P J,Willis P A.From ATP to AZD6140:the discovery of an orally active reversible P2Y12receptor antagonist for the prevention of thrombosis[J].Bioorganic&Medicinal Chemistry Letters,2007,17(21):6013-6018.
8 Zhang H,Liu J,Zhang L,Kong L,Yao H,Sun H.Synthesis and biological evaluation of ticagrelor derivatives as novel antiplatelet agents[J].Bioorganic&Medicinal Chemistry Letters,2012,22(11):3598-3602.
9 Tu W,Fan J,Zhang H,Xu G,Liu Z,Qu J,Yang F,Zhang L,Luan T,Yuan J,Gong A,Feng J,Sun P,Dong Q.Synthesis and biological evaluation of cyclopentyl-triazolol-pyrimidine(CPTP)based P2Y12,antagonists[J].Bioorganic&Medicinal Chemistry Letters,2014,24(1):141-146.
10 Yao G,Su G,Li K,Li B,Dong H.Comparative study of Ticagrelor and Clopidogrel in Therapeutic Effect of Acute Myocardial Infarction Patients Undergoing Percutaneous Coronary Intervention[J].Saudi Journal of Biological Sciences,2017,24(8):818-1820.
11 Zhang S,Hu L,Du H,Guo Y,Zhang Y,Niu H,Jin J,Zhang J,Liu J,Zhang X,Kunapuli S P,Ding Z.BF0801,a novel adenine derivative,inhibits platelet activation via phosphodiesterase inhibition and P2Y12 antagonism[J].Thrombosis&Haemostasis,2010,104(4):845-857.
12 Hu L,Fan Z,Du H,Ni R,Zhang S,Yin K,Ye J,Zhang Y,Wei X,Zhang X,Gross P L,Kunapuli S P,Ding Z.BF061,a novel antiplatelet and antithrombotic agent targeting P2Y??receptor and phosphodiesterase[J].Thrombosis&Haemostasis,2011,106(6):1203-1214.
13 Pan C,Wei X,Ye J,Liu G,Zhang S,Zhang Y,Du H,Ding Z.BF066,a novel dual target antiplatelet agent without significant bleeding[J].Plos One,2012,7(7):e40451.
15 Tuppurainen K,Viisas M,Per?kyl?M,Laatikainen R.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.
16 Verma J,Khedkar V M,Coutinho E C.3D-QSAR in drug design--a review[J].Current Topics in Medicinal Chemistry,2010,10(1):95-115.
18 S Tan,T Wang,H Wang,F Xu.Structure based virtual screening by distributed computing[J].Computers&Applied Chemistry,2015,32(9):1025-1030.
20 Patel H,Noolvi M,Sharma P,Jaiswal V,Bansal S,Lohan S,Kumar S,Abbot V,Dhiman S,Bhardwaj V.Quantitative structure-activity relationship(QSAR)studies as strategic approach in drug discovery[J].Medicinal Chemistry Research,2014,23(12):4991-5007.
21 VM Shahani,P Yue,S Haftchenary,W Zhao,J LLukkarila,X Zhang,D Ball,C Nona,P T Gunning,JTurkson.Identification of purine-scaffold smallmolecule inhibitors of stat3 activation by QSARStudies[J].ACS Medicinal Chemistry Letters,2010,2(1):79-84.
23 Robinson D D,Winn P J,Lyne P D,et al.Selforganizing molecular field analysis:a tool for structureactivity studies[J].Journal of Medicinal Chemistry,1999,42(4):573-583.
24 Ojha P K,Mitra I,Das R N,et al.Further exploring r m2,metrics for validation of QSPR models[J].Chemometrics&Intelligent Laboratory Systems,2011,107(1):194-205.
25 Liu G,Xu J,Chen N,Zhang S,Ding Z,Du H.Synthesis of-alkyl(aryl)-2-alkyl(aryl)thioadenosines as antiplatelet agents[J].European Journal of Medicinal Chemistry,2012,53(19):114-123.
14李顺来,陆成虎,杜洪光.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[J].北京化工大学学报(自然科学版),2017,44(04):8-13.
17文晓荣,王娟,安春红,舒茂,林治华.噻唑类Fascin蛋白抑制剂的3D-QSAR研究[J].计算机与应用化学,2016,33(8):886-890.
19李秀艳,郑艳,李顺来,杜洪光.新型二芳基取代-1,2,4-三唑类化合物的抗炎构效关系和分子对接研究[J].计算机与应用化学,2008,25(5):603-606.
22何琦文.9-取代-6-烷氨基-2-烷硫基嘌呤化合物的合成及抗血小板凝集活性[D].北京化工大学,2012.
26何琦文,杜洪光.9-乙酰氧基乙基-6-烷氨基-2-烷硫基嘌呤的合成及抗血小板凝集活性评估[J].有机化学,2012,32(09):1678-1683.
27汪韬,杜洪光.9-(2-羟基乙基)-6-烷氨基-8-甲氧基-2-烷硫基嘌呤的合成及其抗血小板凝集活性[J].有机化学,2013,33(08):1720-1727.