张燕玲杨晔杨珍乔延江 ** / 目的 : 构建内皮素受体 A(Endothelins A Receptor,ETA) 的拮抗剂药效团模型, 用以搜索中草药数据库, 寻找中药 ETA 受体拮抗剂方法 : 以对鼠主动脉平滑肌细胞的内皮素受体 A 有抑制作用的 36 个化合物为研究对象,

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1 张燕玲杨晔杨珍乔延江 ** / 目的 : 构建内皮素受体 A(Endothelins A Receptor,ETA) 的拮抗剂药效团模型, 用以搜索中草药数据库, 寻找中药 ETA 受体拮抗剂方法 : 以对鼠主动脉平滑肌细胞的内皮素受体 A 有抑制作用的 36 个化合物为研究对象, 分别利用 HipHop 定性药效团模型和 HypoGen 定量药效团模型构建方法, 建立 ETA 受体拮抗剂药效团模型, 利用数据库搜索方法对药效团模型进行优劣评判并用所获得的最优定性和定量药效团模型对中药化学成分数据库进行筛选结果 : 获得最优定性药效团模型具有以下 6 个特征 :1 个芳环基团 1 个负离子基团 3 个疏水基团及 1 个氢键受体, 其综合评判指数 CAI 值为最优定量药效团模型具有以下 6 个特征 :1 个芳环基团 1 个负离子基团 2 个疏水基团 1 个氢键受体以及 1 个排除体积, 其综合评判指数 CAI 值为 45.96, 表明所构建动物模型具有一定的可靠性, 且利用定量药效团模型筛选中药化学成分数据库命中 16 个化学成分结论 : 本文所构建的定性和定量药效团模型筛选效率较高, 可分别开展活性化合物筛选和活性预测研究, 有助于指导发现中药 ETA 受体拮抗剂 : 内皮素受体 A 定性药效团定量药效团 doi: /wst 中图分类号 :Q93-93 文献标识码 :A [ 1] 21 ET A Yanagisawa [2] [7] 1988 ET A ET-1 ET-2 ET-3 ET-1 ET A ET A ET B [3] [4~6] ET A * ** 收稿日期 : 修回日期 : 科学技术部国家科技支撑计划 (2008BAI51B01): 中药有效成分群辨识研究, 负责人 : 张宏桂 ; 北京中医药大学自主课题 (2011-JDJS-11): 基于药效学及功效网络的复方参仙冰组方优化研究, 负责人 : 马群 ; 北京中医药大学自主课题 (2011-JDJS-12): 活血化瘀中药治疗冠心病的作用机制研究, 负责人 : 张燕玲通讯作者 : 乔延江, 本刊编委, 教授, 主要研究方向 : 中药信息学 1. 样本集化合物 Catalyst HipHop 471

2 2013 Vol.15 No.3 HypoGen ET A 1 2 HipHop HipHop HypoGen 4 2. 实验方法 [ 8, 9] 1 化合物前处理 MDDR [10,11] Catalyst Best Quality A ~ nm kj mol ETA 2 18 Catalyst Hydrogen bond 1 ETA 母核结构化合物 R1 R2 R3 R4 IC 50 (nmol L -1 ) 1 COOH COOH COOH COOH COOH 14 6 COOH

3 母核结构化合物 R1 R2 R3 R4 IC 50 (nmol L -1 ) OCH(CH 3 ) 2 COOH OC 2 H 5 COOH OCH(CH 3 ) 2 COOH H COOH OCH(CH 3 ) 2 COOH H H COOH

4 2013 Vol.15 No.3 2 ETA 母核结构化合物 R1 R2 R3 R4 IC 50 (nmol L -1 ) 19 OCH(CH 3 ) 2 C 4 H 9 COOH OCH(CH 3 ) 2 COOH H COOH OCH(CH 3 ) 2 H COOH OCH(CH 3 ) 2 C 4 H 9 CONH OCH(CH 3 ) 2 H COOH

5 母核结构化合物 R1 R2 R3 R4 IC 50 (nmol L -1 ) acceptor A Hydrogen bond acceptor A H 0~5 lipid ALi Hydrogen bond donor D 3 HypoGen 药效团模型的建立 Hydrophobic region H Hydrophobic aliphatic region Hal Hy- drophobic aromatic region Har Nega- A HypoGen [13] tive charge N Negative ionizable NI Positive charge P Excluded Volumes Positive ionizable PI Ring aromatic R 2 HipHop 药效团模型的建立 HipHop [12] 1 4 药效团模型优劣评价 12 Principal 2 MaxOmitFit 0 Principal MaxOmitFit R NI 1~5 EV 1 HypoRefine 95% 10 1 D 1 A Ha NI A NI 1~5 Ht D 475

6 2013 Vol.15 No.3 NI 3 H 1 A HipHop A%=(Ha/A) HypoGen 药效团模型的建立 2 10 CAI Comprehensive Appraisal Index =N A% 5 数据库搜索 Fast Flexible Database Search Traditional Chinese Medicine Database TCMD Best fit/compare 1 Fit H1 1. HipHop 药效团模型 H2 A Hierarchical cluster analysis HCA NI H H H A A 2 3~6 H3 R NI H H H A 3 10 NI H H H H A 10 NI 3 D= A=100 3 CAI N R 1 2 ETA HipHop A2 3 ET A HipHop Hypo Features Rank Ha Ht A% N CAI 1 NI H H H A A NI H H H A A R NI H H H A R NI H H H A R NI H H H A R NI H H H A NI H H H A A NI H H H A A NI H H H A A NI H H H H A

7 ~ Cost RMS Correlation % 0.6 cost % 0.9 [14,15] 10 RMS D= A= ETA 受体拮抗剂药效团搜索结果 H 1 A 1 HipHop 6 R 1 N 1 TCMD HypoGen EV TCMD Fisher 4 ET A HypoGen Hypo Features Ev Corrtrain Corrtest Cost TotalCost 11 A H H NI R A H H NI R A H H NI R A H NI R A H H NI R A H H NI R A H H NI R A H H NI R A H H NI R A H H NI R ET A 10 Hypo Features EV Ha Ht A% N CAI 11 A H H N R A H H N R A H H N R A H N R A H H N R A H H N R A H H N R A H H N R A H H N R A H H N R

8 2013 Vol.15 No.3 ETA B [ 16, 17] ETA 4 B ETA 120nM B ET A Endotholin ET B ET A ET-1 ET A ET A Clazosentan [18~20] ET A ET A 3 ETA HypoGen 6 ET A 11 Name Fita Mappingb IC 50 (nmol L -1 ) Errorc Est Act [ ] [ ] [ *] [ ] [* ] [9 29 * 15 22] [34 19 * 21 11] [32 26 * 13 16] [24 28 * 13 5] [24 33 * 13 1] [27 31 * 13 16] [* * 16] [34 25 * 11 18] [33 24 * 11 17] [20 29 * 11 22] [42 * * 14 1] [* 27 * 23 17] [* 5 * * 11] a) the inosculated degree of pharmocophore model with the related compounds; b) the matching degree of pharmacophore with the specific conformation of the compounds; the asterisk (*)means no matching with pharmacophore element; c) the ratio of estimated activity to actual activity. "+" and "-" represent positive and negative errors, respectively. 478

7 ET A CatScramble Corr RMS TotalCost FixedCost NullCost ΔCost Config Results for unscrambled 0.926 8 1.250 7 95.01 78.05 157.41 62.40 16.38 Results for scrambled 1 0.794 7 2.024 7 118.52 76.98 157.

9 7 ET A CatScramble Corr RMS TotalCost FixedCost NullCost ΔCost Config Results for unscrambled Results for scrambled CAI , B ETA ET A 479

10 2013 Vol.15 No.3 1 Sakurai T, Yanagisawa M, M asaki T. Molecular characterization of dioxol yl ) isopropyloxy ( 4 - methoxyphenyl ) - 2H - endothelin receptors. Trends Pharmacol Sci, 1992,13(3) 103~108. chromene-3-carboxylic Acid (S-1255). 1. Study on structure-activity 2 Rossi G P, Seccia T M, Albertin G, et al. Measurement of endothelin: clinical and research use. Ann Clin Biochem, 2000, 37(Pt5) 608~626. relationships and basic structure crucial for ET(A) antagonism. J Med Chem, 2002, 45(10) 2041~ Oliver F F, Viktor K, Jan D, et al. Chemical function based pharmacophore generation of endothelin -A selective receptor antago- 3 Nilsson D, Wackenfors A, Gustafsson L, et al. Endothelin receptormediated vasodilatation: Effects of organ culture. Eur J Pharmacol, nists. J Med Chem, 2004, 47(11) 2750~ ,579(1/3) 233~ Aparoy P, Kumar Reddy K, Kalanqi S K, et al. Pharmacophore 4,,,. modeling and virtual screening for designing potential 5 -Lipoxygenase inhibitors. Bioorg Med Chem Lett, 2010, 20(3) 1013~1018. ( )., 2009, 44(9) 1002~ Joan R, Cucarull -G, Christian L. Influence of the Conditions in 13 Catalyst, Version 4.11, Accelrys, Inc, San Diego, CA, pharmacophore generation, scoring, and 3D database search for 14. chemical feature -based pharmacophore models: one application study of ETA - and ETB -selective antagonists. Chem Inf Model, 2006, 46(3) 1439~1455., ~19. 15,,.5-HT3., 2008, 29(6) 1125~ ,,. B, ,. B., 2008, 14(12) 1799~ Han B S, Gai L Y. Advancement in research of endothelin type B receptor in the cardiovascular system. Medical Recapitulate, 2008, 14(12) 1799~ Bao H J, Zhang Y L, Qiao Y J. Pharmacophore model generation of HMG-CoA reductase inhibitors. Acta Phys Chim Sin, 2008, 24(2) Liu F, You Q D, Chen Y D. Pharmacophore indentification of KSP inhibitors. Bioorg Med Chem Lett, 2007, 17(3) 722~ Ishizuka N, Matsumara K, Sakai K, et al. Structure -activity relationships of a novel class of endothelin -A receptor antagonists and discovery of potent and selective receptor antagonist,2 -(Benzo [1,3]., 2009, 29(9) 2346~ B., 2010, 30(21) 3113~ /., Jens L, Alexander O, Michael B, et al. Structural determinats for selective recognition of peptide ligands for endothelin receptor subtypes ETA and ETB. J Pept Sci, 2009, 15(7) 479~ ,,,. ET_A ETP- 508., 2009, 25(11) 1465~1469. Pharmacophore Model Construction of Endothelins A Receptor Antagonist Zhang Yanling 1, 2, Yang Ye 1, 2, Yang Zhen 1, 2, Qiao Yanjiang 1, 2 (1. Research Center of TCM-information Engineering, Beijing University of Chinese Medicine, Beijing , China; 2. Beijing Key Laboratory of Foundational Research and Drug Development of Traditional Chinese Medicine, Beijing , China) Abstract: This study was aimed to construct the pharmacophore models of endothelins A receptor antagonist in the application of screening traditional Chinese medicine (TCM) database for novel ETA Receptor antagonists. Qualitative and quantitative hypotheses were generated by HipHop and HypoGen separately on the basis of 36 compounds with antagonistic action on Endothelins A Receptor expressed in the aortic smooth muscle cells of rats. Database searching method was used to evaluate the generated hypotheses. The optimum hypotheses were used to search TCM database. The results showed that optimum qualitative hypothesis is with six features, which were one aromatic ring, one hydrogen-bond acceptors, one negative ionizable group and three hydrophobic groups, and the CAI value of The optimum quantitative hypothesis is with six features, which were one aromatic ring, one 480

11 hydrogen-bond acceptor, one negative ionizable group, two hydrophobic groups and one exclusive volume, and the CAI value of Sixteen compounds from TCM were found in the database searching with the quantitative hypothesis. It was concluded that the pharmacophores are reliable and can be used to screen database for novel E- TA inhibitors. The qualitative and quantitative hypothesis can be used to screen database for active compounds and to predict the activity respectively. Keywords: Endothelins A receptor, qualitative pharmacophore, quantitative pharmacophore ( 责任编辑 : 李沙沙张志华, 责任译审 : 王晶 ) 481

1. 血府逐瘀汤化学成分集 COX-2 Cyclooxyenase-2 99 Corticotropin-releading [3] 65 hormone, CRH HDAC [4] 92 2 Cyclin-dependent Kinase, CDK2 /CyclinA Glutam

1. 血府逐瘀汤化学成分集 COX-2 Cyclooxyenase-2 99 Corticotropin-releading [3] 65 hormone, CRH HDAC [4] 92 2 Cyclin-dependent Kinase, CDK2 /CyclinA Glutam * 张燕玲黄明峰王元明高静乔延江 ** / 100102 本文利用中药有效成分族辨识技术, 针对血府逐瘀汤中 668 个化学成分进行了活性辨识, 命中化合物达到 213 个命中靶标为 20 个采用 Cytoscape 软件建立药物 - 靶点相互作用网络模型, 并探讨其多成分 - 多靶点 - 多疾病相关关系研究结果表明, 血府逐瘀汤活性成分可调控 ACE AngII TNFα COX 2 5-LOX