应用分子对接方法探讨了多溴二苯醚（ PBDE）衍生物与人胎盘芳香化酶间的可能作用机理。通过分析对接生成的构象发现，羟基多溴二苯醚（ HO?PBDEs）和甲氧基多溴二苯醚（ MeO?PBDEs）与人胎盘芳香化酶间形成氢键的情况不同。对人胎盘芳香化酶有抑制活性的 HO?PBDEs 通过其羟基（—OH）与氨基酸残基Arg435、Arg115、Arg375、Asp309和Ala306形成氢键，而对人胎盘芳香化酶无抑制活性的MeO?PBDEs的甲氧基（ MeO—）几乎不与芳香化酶内氨基酸残基形成氢键，这可能是二者对芳香化酶抑制活性不同的原因。由此推测，化合物作为氢键供体可能是多溴二苯醚衍生物具有抑制芳香化酶活性的结构基础。本研究从化合物结构及化合物与人胎盘芳香化酶结合的构象特征上解释化合物活性不同的原因，以期能够利用构象分析得到的结果进行筛选。
Intermolecular interaction between polybrominated diphenyl ether ( PBDE ) derivatives and human placental aromatase was explored based on molecular docking.This study revealed that the H?bond interactions between PBDE derivatives and aromatase are different. HO?PBDEs, having significant inhibition on placental aromatase activity, formed H?bonds between—OH and amino acid residues Arg435, Arg115, Arg375, Asp309 and Ala306. MeO?PBDEs, not having inhibition activity on aromatase enzyme, did not form H?bond between MeO— and amino acid residues. So it was presumed that hydrogen bond donor may be the structural basis of PBDE derivatives having aromatase inhibition. The present study explored the structural and conformational requirements of PBDE derivatives with different aromatase inhibition activities.It is hoped that further screening can be carried out by analyzing the poses derived from molecular docking.
参考文献
| [1] | 万斌,郭良宏.多溴联苯醚的环境毒理学研究进展[J].环境化学,2011(01):143-152. |
| [2] | 张利飞,黄业茹,董亮.多溴联苯醚在中国的污染现状研究进展[J].环境化学,2010(05):787-795. |
| [3] | 赵恒,孟祥周,向楠,李宇霖,温智皓,陈玲.上海市受纳污水河流中多溴联苯醚的生态风险评价[J].环境化学,2012(05):573-579. |
| [4] | 黄飞飞,李敬光,赵云峰,吴永宁.我国沿海地区贝类样品中十溴联苯醚污染水平分析[J].环境化学,2011(02):418-422. |
| [5] | Legler J;van den-Brink-CE;Brouwer A;Murk AJ;van der-Saag-PT;Vethaak AD;van der-Burg-B .Development of a stably transfected estrogen receptor-mediated luciferase reporter gene assay in the human T47D breast cancer cell line.[J].Toxicological sciences: An official journal of the Society of Toxicology,1999(1):55-66. |
| [6] | Meerts I A;Letcher R J;Hoving S et al.In vitro estrogenicity of polybrominateddiphenylethers,hydroxylated PDBEs,and polybrominated bisphenol A compounds[J].Environmental Health Perspectives,2001,109:399-407. |
| [7] | Hamers T;Kamstra JH;Sonneveld E;Murk AJ;Kester MH;Andersson PL;Legler J;Brouwer A .In vitro profiling of the endocrine-disrupting potency of brominated flame retardants.[J].Toxicological sciences: An official journal of the Society of Toxicology,2006(1):157-173. |
| [8] | Mercado-Feliciano M;Bigsby RM .Hydroxylated metabolites of the polybrominated diphenyl ether mixture DE-71 are weak estrogen receptor-alpha ligands.[J].Environmental health perspectives,2008(10):1315-1321. |
| [9] | Kojima H;Takeuchi S;Uramaru N .Nuclear hormone receptor activity of polybrominated diphenyl ethers and their hydroxylated and methoxylated metabolites in transactivation assays using Chinese hamster ovary cells.[J].Environmental health perspectives,2009(8):1210-1218. |
| [10] | Shigeyuki Kitamura;Seiji Shinohara;Eri Iwase;Kazumi Sugihara;Naoto Uramaru;Hidenari Shigematsu .Affinity for Thyroid Hormone and Estrogen Receptors of Hydroxylated Polybrominated Diphenyl Ethers[J].Journal of health science,2008(5):607-614. |
| [11] | Canton RF;Sanderson JT;Letcher RJ;Bergman A;van den Berg M .Inhibition and induction of aromatase (CYP19) activity by brominated flame retardants in H295R human adrenocortical carcinoma cells.[J].Toxicological sciences: An official journal of the Society of Toxicology,2005(2):447-455. |
| [12] | Canton RF;Scholten DE;Marsh G;de-Jong PC;van-den-Berg M .Inhibition of human placental aromatase activity by hydroxylated polybrominated diphenyl ethers (OH-PBDEs).[J].Toxicology and Applied Pharmacology,2008(1):68-75. |
| [13] | 杨伟华,胡伟,冯政,刘红玲,于红霞.多溴二苯醚及其代谢物的内分泌干扰活性和构效关系研究进展[J].生态毒理学报,2009(02):164-173. |
| [14] | 杨伟华,于红霞.多溴二苯醚类化合物干扰人雌激素受体alpha活性机理的理论研究[J].环境化学,2013(07):1168-1179. |
| [15] | 付静,沈中华,程飞雄,刘桂霞,李卫华,唐赟.芳香化酶的结构、催化机制及其抑制剂研究进展[J].药学学报,2012(01):18-28. |
| [16] | Holger Gohlke;Gerhard Klebe .DrugScore Meets CoMFA: Adaptation of Fields for Molecular Comparison (AFMoC) or How to Tailor Knowledge-Based Pair-Potentials to a Particular Protein[J].Journal of Medicinal Chemistry,2002(19):4153-4170. |
| [17] | Ewing TJA.;Skillman AG.;Kuntz ID.;Makino S. .DOCK 4.0: Search strategies for automated molecular docking of flexible molecule databases[J].Journal of Computer-Aided Molecular Design,2001(5):411-428. |
| [18] | Sanderson JT;Hordijk J;Denison MS;Springsteel MF;Nantz MH;van den Berg M .Induction and inhibition of aromatase (CYP19) activity by natural and synthetic flavonoid compounds in H295R human adrenocortical carcinoma cells.[J].Toxicological sciences: An official journal of the Society of Toxicology,2004(1):70-79. |
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