芦荟有效成分与子宫内膜癌相关蛋白分子对接及药物特性
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摘要
通过计算机辅助药物设计的方法,研究草药芦荟中的成分对子宫内膜癌相关蛋白如AKT1,mTOR,VEGFR2的结合能力并分析其中的潜在有效成分作为子宫内膜癌的抗癌药物的可能性。运用Surflex-Dock和ACD/Labs Percepta Profilers软件对芦荟中的33种成分与3个已知蛋白质结构进行柔性分子对接和ADMET的预测,并分析其打分函数和结合位点的对接情况。结果显示对接得分高且ADMET特性好的为Aloenin,其它得分较好的有7-(beta-Xylosyl)cephalomannine和Chrysophanol8-O-beta-D-(6'-O-malontl)glucopyranoside,而Aloenin具有最好的潜在药物特性,可做相关的生物活体和临床相关研究来进一步了解它的确切功效,从而研发一种治疗子宫内膜癌的新药。
Using Computer-aided drug design(CADD) technologies to explore the drug properties and binding abilities of the herbal ingredients of aloe vera in endometrial cancer related protein, including AKT1, m TOR and VEGFR2. Surflex-Dock and ACD/Labs Percepta Profilers were used to perform flexible docking and ADMET prediction. The results of this study reported the compound Aloenin has good ADMET properties and achieved high docking score among the 3 targeted proteins. 7-(beta-Xylosyl)cephalomannine and Chrysophanol 8-O-beta-D-(6'-O-malontl) glucopyranoside also have high score, but Aloenin has the best potential for further in vitro and in vivo studies, which may lead to the discovery of new drug using in the treatment of endometrial cancer.
Using Computer-aided drug design(CADD) technologies to explore the drug properties and binding abilities of the herbal ingredients of aloe vera in endometrial cancer related protein, including AKT1, m TOR and VEGFR2. Surflex-Dock and ACD/Labs Percepta Profilers were used to perform flexible docking and ADMET prediction. The results of this study reported the compound Aloenin has good ADMET properties and achieved high docking score among the 3 targeted proteins. 7-(beta-Xylosyl)cephalomannine and Chrysophanol 8-O-beta-D-(6'-O-malontl) glucopyranoside also have high score, but Aloenin has the best potential for further in vitro and in vivo studies, which may lead to the discovery of new drug using in the treatment of endometrial cancer.
引文
1 Colombo N,Preti E,Landoni F,Carinelli S,Colombo A,Marini C&Sessa C,On behalf of the ESMO Guidelines Working Group.Endometrial cancer:ESMO clinical practice guidelines for diagnosis,treatment and follow-up[J].Annals of Oncology,2011,22(6):35-39.
2 Zagouri F,Bozas G,Kafantari E,Tsiatas M,Nikitas N,Dimopoulos M A&Papadimitriou C A.Endometrial cancer:What is new in adjuvant and molecularly targeted therapy?[J]Obstetrics and Gynecology International,2010,2010:749579.
3 Westin S N&Broaddus R R.Personalized therapy in endometrial cancer:Challenges and opportunities[J].Cancer Biology&Therapy.Cancer biology&therapy,2012,13(1):1-13.
4 Gary Hudes M D,Michael Carducci M D,Piotr Tomczak M D,Janice Dutcher M D,Robert Figlin M D,Anil Kapoor M D,Elzbieta Staroslawska M D,Jeffrey Sosman M D,David Mc Dermott M D,István Bodrogi M D,Zoran Kovacevic M D,Vladimir Lesovoy M D,Ingo G H,Schmidt-Wolf M D,Olga Barbarash M D,Erhan Gokmen M D,Timothy O'Toole M S,Stephanie Lustgarten M S,Laurence Moore M D,Ph D and Robert J,Motzer M D for the Global ARCC Trial.Temsirolimus,interferon alfa,or both for advanced renal-cell carcinoma[J].The New England Journal of Medicine,2007,356(22):2271-2281.
5 Crul M,Rosing H,de Klerk G J,Dubbelman R,Traiser M,Reichert S,Knebel N G.,Schellens J H,Beijnen J H,ten Bokkel Huinink W W.Phase I and pharmacological study of daily oral administration of perifosine(D-21266)in patients with advanced solid tumours[J].European Journal of Cancer(Oxford,England:1990),2002,38(12):1615-1621.
6 Burris H,Rodon J,Sharma S,Herbst R S,Tabernero J,Infante J R,Silva A,Demanse D,Hackl W and Baselga J.First-in-human phase I study of the oral PI3K inhibitor BEZ235 in patients(pts)with advanced solid tumors[J].Journal of Clinical Oncology,2010,28(15).
7 Biton V,Mirza W,Montouris G,Vuong A,Hammer A E&Barrett P S.Weight change associated with valproate and lamotriginemonotherapy in patients with epilepsy[J].Neurology,2001,56(2):172-177.
8 Martin Schlumberger,Makoto Tahara,Lori J Wirth,Bruce Robinson,Marcia S Brose,Rossella Elisei,Corina E Dutcus,Bego?a de las Heras,Junming Zhu,Mouhammed Amir Habra,Kate Newbold,Manisha H Shah,Ana O Hoff,Andrew GGianoukakis,Naomi Kiyota,Matthew Hiram Taylor,Sung-Bae Kim,Monika K Krzyzanowska and Steven I Sherman.A phase 3,multicenter,double-blind,placebo-controlled trial of lenvatinib(E7080)in patients with 131I-refractory differentiated thyroid cancer(SELECT)[J].Journal of Clinical Oncology,2014,32(18).
9 Ron J Keizer,Anubha Gupta,Robert Shumaker,Jos H Beijnen,Jan H M Schellens and Alwin D R Huitema.Model-based treatment optimization of a novel VEGFR inhibitor[J].Br JClin Pharmacol,2012,74(2):315-326.
11 Hou Chunzhe,Shao Shuli.The function of chinese medicine in the cancer treatment[J].Journal of Science of Teachers′College and University,2009,29(1):86-89.
13 Wang Xiangzheng,Li Yingyong,Sun Xianbin.Effect of aloe on survivin expression in endometrial carcinoma[J].Journal of Guang Dong Medical College,2006,24(4):355-356.
14 Ajay N Jain.Surflex:?fully automatic flexible molecular docking using a molecular similarity-based search engine[J].Journal of Medical Chemistry,2003,46(4):499-511.
15 Lv Juan.QSAR and molecular design studies of proteasome inhibitors.2012.
16 Ashwell Mark A,Lapierre Jean-Marc,Brassard Christopher,Bresciano Karen,Bull Cathy,Cornell-Kennon Susan,Eathiraj Sudharshan,France Dennis S,Hall Terence,Hill Jason,Kelleher Eoin,Khanapurkar Sampada,Kizer Darin,Koerner Steffi,Link Jeff,Liu Yanbin,Makhija Sapna,Moussa Magdi,Namdev Nivedita,Nguyen Khanh,Nicewonger Robert,Palma Rocio,Szwaya Jeff,Tandon Manish,Uppalapati Uma,Vensel David,Volak Laurie P,Volckova Erika,Westlund Neil,Wu Hui,Yang Rui-Yang,Chan Thomas C K.Discovery and optimization of a series of 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amines:Orally bioavailable,selective,and potent ATP-independent akt inhibitors[J].Journal of Medicinal Chemistry,2012,55(11):5291-5310.
17 Yang Haijuan,Rudge Derek G,Koos Joseph D,Vaidialingam Bhamini,Yang Hyo J,Pavletich Nikola P.m TOR kinase structure,mechanism and regulation[J].Nature,2013,497(7448):217-223.
18 Mc Tigue M,Murray B W,Chen J H,Deng Y,Solowiej J&Kania R S.Molecular conformations,interactions,and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors[J].Proceedings of the national academy of sciences of the united states of america,2012,109(45):18281-18289.
19 Wu Xiaofang,Wan Jinzhi,Luo Bingjun,Yang Miaorong,Ding Wenjing,Zhong Jiasheng.A novel naphthalene derivative from aloe barbadensis[J].Acta Pharmaceutica Sinica,2013,48(5):723-727.
20 Chen C Y.TCM Database@Taiwan:The World's Largest Traditional Chinese Medicine Database for Drug Screening In Silico,PLo S ONE,2011,6(1):e15939.
21 Harry E Pence,Antony Williams.Chem Spider:An online chemical information resource[J].Journal of Chemical Education,2012,87(11):1123-1124.
22 Qi Z,Yanrui D,Jun S,Wei F,Wenbo X.Research on flexible molecular docking problem using QPSO algorithm[J].Computers and Applied Chemistry,2010,27(7):963-966.
23 Lape M,Elam C&Paula S.Comparison of current docking tools for the simulation of inhibitor binding by the transmembrane domain of the sarco/endoplasmic reticulum calcium ATPase[J].Biophysical Chemistry,2010,150(1-3):88-97.
24 Irwin J J&Shoichet B K.ZINC--a free database of commercially available compounds for virtual screening[J].Journal of Chemical Information and Modeling,2005,45(1):177-182.Retrieved from
25 Van d W&Gifford E.ADMET in silico modelling:Towards prediction paradise?[J]Nature Reviews.Drug Discovery,2003,2(3):192-204.
26 Lagorce D,Sperandio O,Galons H,Miteva M A&Villoutreix BO.FAF-Drugs2:Free ADME/tox filtering tool to assist drug discovery and chemical biology projects[J].BMC Bioinformatics,2008,9:396-396.
27 ACD/Labs Percepta Profilers,Advanced Chemistry Development,Inc.Toronto,Ont,Canada www.acdlabs.com,2015.
28 Repasky M P,Murphy R B,Banks J L,Greenwood J R,Tubert-Brohman I,Bhat S&Friesner R A.Docking performance of the glide program as evaluated on the astex and DUD datasets:A complete set of glide SP results and selected results for a new scoring function integrating Water Map and glide[J].Journal of Computer-Aided Molecular Design,2012,26(6):787-799.
29 Lu Baiyi,Yang Jiajia,Xiong Lina.Bioactivity,synthesis,extraction and analysis of sterol ferulate:A review[J].Modern Food Science and Technology,2013,29(12):3063-3069.
30 Wang T,Hicks K B,Moreau R.Antioxidant activity of phytosterols,oryzanol,and other phytosterol conjugates JAOCS,2002,79(12):1201-1206.
31 Tian Yuanyuan,Lin Qinlu,Luo Feijun.New progress on physiological functions ofγ-oryzanol from rice bran[J].Journal of Cereals&Oils,2013,26(6):43-46.
32 Kim S P,Kang M Y,Nam S H&Friedman M.Dietary rice bran componentγ-oryzanol inhibits tumor growth in tumor-bearing mice[J].Molecular Nutrition&Food Research,2012,56(6):935-944.
34 Jin G.,Quan H,Koyanagi J,Takeuchi K,Miura Y,Komada F&Saito S.4'-O-alkyaloenin derivatives and their sulfates directed toward overcoming multidrug resistance in tumor cells[J].2005,218(1):15-20.
10宋云娟,龙风昌.临床几种常用抗癌中药研究概述[J].云南中医中药杂志,1997,18(1):51-52.
12孙聪聪,张英姿.中药抗子宫内膜癌在实验研究领域的新进展[J].滨州医学院学报,2012,35(1):61-63.
33黄东纬,叶伟业.芦荟抗肿瘤活性成分研究进展[J].中国现代药物应用,2011,5(6):187-188.
2 Zagouri F,Bozas G,Kafantari E,Tsiatas M,Nikitas N,Dimopoulos M A&Papadimitriou C A.Endometrial cancer:What is new in adjuvant and molecularly targeted therapy?[J]Obstetrics and Gynecology International,2010,2010:749579.
3 Westin S N&Broaddus R R.Personalized therapy in endometrial cancer:Challenges and opportunities[J].Cancer Biology&Therapy.Cancer biology&therapy,2012,13(1):1-13.
4 Gary Hudes M D,Michael Carducci M D,Piotr Tomczak M D,Janice Dutcher M D,Robert Figlin M D,Anil Kapoor M D,Elzbieta Staroslawska M D,Jeffrey Sosman M D,David Mc Dermott M D,István Bodrogi M D,Zoran Kovacevic M D,Vladimir Lesovoy M D,Ingo G H,Schmidt-Wolf M D,Olga Barbarash M D,Erhan Gokmen M D,Timothy O'Toole M S,Stephanie Lustgarten M S,Laurence Moore M D,Ph D and Robert J,Motzer M D for the Global ARCC Trial.Temsirolimus,interferon alfa,or both for advanced renal-cell carcinoma[J].The New England Journal of Medicine,2007,356(22):2271-2281.
5 Crul M,Rosing H,de Klerk G J,Dubbelman R,Traiser M,Reichert S,Knebel N G.,Schellens J H,Beijnen J H,ten Bokkel Huinink W W.Phase I and pharmacological study of daily oral administration of perifosine(D-21266)in patients with advanced solid tumours[J].European Journal of Cancer(Oxford,England:1990),2002,38(12):1615-1621.
6 Burris H,Rodon J,Sharma S,Herbst R S,Tabernero J,Infante J R,Silva A,Demanse D,Hackl W and Baselga J.First-in-human phase I study of the oral PI3K inhibitor BEZ235 in patients(pts)with advanced solid tumors[J].Journal of Clinical Oncology,2010,28(15).
7 Biton V,Mirza W,Montouris G,Vuong A,Hammer A E&Barrett P S.Weight change associated with valproate and lamotriginemonotherapy in patients with epilepsy[J].Neurology,2001,56(2):172-177.
8 Martin Schlumberger,Makoto Tahara,Lori J Wirth,Bruce Robinson,Marcia S Brose,Rossella Elisei,Corina E Dutcus,Bego?a de las Heras,Junming Zhu,Mouhammed Amir Habra,Kate Newbold,Manisha H Shah,Ana O Hoff,Andrew GGianoukakis,Naomi Kiyota,Matthew Hiram Taylor,Sung-Bae Kim,Monika K Krzyzanowska and Steven I Sherman.A phase 3,multicenter,double-blind,placebo-controlled trial of lenvatinib(E7080)in patients with 131I-refractory differentiated thyroid cancer(SELECT)[J].Journal of Clinical Oncology,2014,32(18).
9 Ron J Keizer,Anubha Gupta,Robert Shumaker,Jos H Beijnen,Jan H M Schellens and Alwin D R Huitema.Model-based treatment optimization of a novel VEGFR inhibitor[J].Br JClin Pharmacol,2012,74(2):315-326.
11 Hou Chunzhe,Shao Shuli.The function of chinese medicine in the cancer treatment[J].Journal of Science of Teachers′College and University,2009,29(1):86-89.
13 Wang Xiangzheng,Li Yingyong,Sun Xianbin.Effect of aloe on survivin expression in endometrial carcinoma[J].Journal of Guang Dong Medical College,2006,24(4):355-356.
14 Ajay N Jain.Surflex:?fully automatic flexible molecular docking using a molecular similarity-based search engine[J].Journal of Medical Chemistry,2003,46(4):499-511.
15 Lv Juan.QSAR and molecular design studies of proteasome inhibitors.2012.
16 Ashwell Mark A,Lapierre Jean-Marc,Brassard Christopher,Bresciano Karen,Bull Cathy,Cornell-Kennon Susan,Eathiraj Sudharshan,France Dennis S,Hall Terence,Hill Jason,Kelleher Eoin,Khanapurkar Sampada,Kizer Darin,Koerner Steffi,Link Jeff,Liu Yanbin,Makhija Sapna,Moussa Magdi,Namdev Nivedita,Nguyen Khanh,Nicewonger Robert,Palma Rocio,Szwaya Jeff,Tandon Manish,Uppalapati Uma,Vensel David,Volak Laurie P,Volckova Erika,Westlund Neil,Wu Hui,Yang Rui-Yang,Chan Thomas C K.Discovery and optimization of a series of 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amines:Orally bioavailable,selective,and potent ATP-independent akt inhibitors[J].Journal of Medicinal Chemistry,2012,55(11):5291-5310.
17 Yang Haijuan,Rudge Derek G,Koos Joseph D,Vaidialingam Bhamini,Yang Hyo J,Pavletich Nikola P.m TOR kinase structure,mechanism and regulation[J].Nature,2013,497(7448):217-223.
18 Mc Tigue M,Murray B W,Chen J H,Deng Y,Solowiej J&Kania R S.Molecular conformations,interactions,and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors[J].Proceedings of the national academy of sciences of the united states of america,2012,109(45):18281-18289.
19 Wu Xiaofang,Wan Jinzhi,Luo Bingjun,Yang Miaorong,Ding Wenjing,Zhong Jiasheng.A novel naphthalene derivative from aloe barbadensis[J].Acta Pharmaceutica Sinica,2013,48(5):723-727.
20 Chen C Y.TCM Database@Taiwan:The World's Largest Traditional Chinese Medicine Database for Drug Screening In Silico,PLo S ONE,2011,6(1):e15939.
21 Harry E Pence,Antony Williams.Chem Spider:An online chemical information resource[J].Journal of Chemical Education,2012,87(11):1123-1124.
22 Qi Z,Yanrui D,Jun S,Wei F,Wenbo X.Research on flexible molecular docking problem using QPSO algorithm[J].Computers and Applied Chemistry,2010,27(7):963-966.
23 Lape M,Elam C&Paula S.Comparison of current docking tools for the simulation of inhibitor binding by the transmembrane domain of the sarco/endoplasmic reticulum calcium ATPase[J].Biophysical Chemistry,2010,150(1-3):88-97.
24 Irwin J J&Shoichet B K.ZINC--a free database of commercially available compounds for virtual screening[J].Journal of Chemical Information and Modeling,2005,45(1):177-182.Retrieved from
25 Van d W&Gifford E.ADMET in silico modelling:Towards prediction paradise?[J]Nature Reviews.Drug Discovery,2003,2(3):192-204.
26 Lagorce D,Sperandio O,Galons H,Miteva M A&Villoutreix BO.FAF-Drugs2:Free ADME/tox filtering tool to assist drug discovery and chemical biology projects[J].BMC Bioinformatics,2008,9:396-396.
27 ACD/Labs Percepta Profilers,Advanced Chemistry Development,Inc.Toronto,Ont,Canada www.acdlabs.com,2015.
28 Repasky M P,Murphy R B,Banks J L,Greenwood J R,Tubert-Brohman I,Bhat S&Friesner R A.Docking performance of the glide program as evaluated on the astex and DUD datasets:A complete set of glide SP results and selected results for a new scoring function integrating Water Map and glide[J].Journal of Computer-Aided Molecular Design,2012,26(6):787-799.
29 Lu Baiyi,Yang Jiajia,Xiong Lina.Bioactivity,synthesis,extraction and analysis of sterol ferulate:A review[J].Modern Food Science and Technology,2013,29(12):3063-3069.
30 Wang T,Hicks K B,Moreau R.Antioxidant activity of phytosterols,oryzanol,and other phytosterol conjugates JAOCS,2002,79(12):1201-1206.
31 Tian Yuanyuan,Lin Qinlu,Luo Feijun.New progress on physiological functions ofγ-oryzanol from rice bran[J].Journal of Cereals&Oils,2013,26(6):43-46.
32 Kim S P,Kang M Y,Nam S H&Friedman M.Dietary rice bran componentγ-oryzanol inhibits tumor growth in tumor-bearing mice[J].Molecular Nutrition&Food Research,2012,56(6):935-944.
34 Jin G.,Quan H,Koyanagi J,Takeuchi K,Miura Y,Komada F&Saito S.4'-O-alkyaloenin derivatives and their sulfates directed toward overcoming multidrug resistance in tumor cells[J].2005,218(1):15-20.
10宋云娟,龙风昌.临床几种常用抗癌中药研究概述[J].云南中医中药杂志,1997,18(1):51-52.
12孙聪聪,张英姿.中药抗子宫内膜癌在实验研究领域的新进展[J].滨州医学院学报,2012,35(1):61-63.
33黄东纬,叶伟业.芦荟抗肿瘤活性成分研究进展[J].中国现代药物应用,2011,5(6):187-188.