Enantioselective drug-protein interaction between mexiletine and plasma protein
文献类型：期刊论文
| 作者 | Yu, Lushan1; Hong, Yanjun1; Li, Li1; Jin, Yingxiu1; Zheng, Mingyue2 ; Jiang, Hualiang2; Zeng, Su1
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| 刊名 | JOURNAL OF PHARMACY AND PHARMACOLOGY
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| 出版日期 | 2012-06 |
| 卷号 | 64期号:6页码:792-801 |
| 关键词 | a1-acid glycoprotein enantioselectivity human serum albumin mexiletine molecular dynamics |
| ISSN号 | 0022-3573 |
| DOI | 10.1111/j.2042-7158.2012.01487.x |
| 文献子类 | Article |
| 英文摘要 | Objectives This study examined the interaction of mexiletine enantiomers with human plasma, human serum albumin (HSA), and human a1-acid glycoprotein (hAGP), and characterized the binding modes of mexiletine enantiomers with hAGP in the molecular level. Methods Enantiomer separation of mexiletine was performed using precolumn derivatization chiral HPLC. The ultrafiltration technique was used to separate the free mexiletine in plasma matrix. Molecular dynamics simulations and free energy calculations were assessed using molecular mechanics and the generalized Born surface area method. Key findings Significant differences in enantioselective binding to human plasma were observed (R > S). The hAGPmexiletine binding profile exhibited similar enantioselectivity (R > S) to that in human plasma, whereas HSAmexiletine interaction was S > R at pH 7.4. Moreover, the results of comparative studies indicated that mexiletine had the highest binding affinity for F1-S, a variant of hAGP. Based on the computational studies, residues such as Arg90, Leu79, Ser89 and Phe89 showed an energy difference of more than -0.35 kcal/mol between the enantiomers. Conclusions hAGP may be one of the key proteins leading to the enantioselective protein bindings of mexiletine in human plasma (R > S). The residues Arg90, Leu79, Ser89 and Phe89 of hAGP may have important roles in the observed enantioselectivity. |
| WOS关键词 | HUMAN ALPHA(1)-ACID GLYCOPROTEIN ; MOLECULAR-MECHANICS ; CONTINUUM MODELS ; FORCE-FIELD ; BINDING ; ENANTIOMERS ; PHARMACOKINETICS ; VARIANTS |
| 资助项目 | National Basic Research Program of China (973 Program)[2011CB710802] ; Ministry of Science and Technology of China[2012ZX09506001-004] ; Ministry of Science and Technology of China[2009ZX09304-003] ; Fundamental Research Funds for the Central Universities[00000000] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000303858200004 |
| 出版者 | WILEY-BLACKWELL |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278071]  |
| 专题 | 药物发现与设计中心 |
| 通讯作者 | Zeng, Su |
| 作者单位 | 1.Zhejiang Univ, Dept Pharmaceut Anal & Drug Metab, Coll Pharmaceut Sci, Hangzhou 310058, Zhejiang, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 200031, Peoples R China |
| 推荐引用方式 GB/T 7714 | Yu, Lushan,Hong, Yanjun,Li, Li,et al. Enantioselective drug-protein interaction between mexiletine and plasma protein[J]. JOURNAL OF PHARMACY AND PHARMACOLOGY,2012,64(6):792-801. |
| APA | Yu, Lushan.,Hong, Yanjun.,Li, Li.,Jin, Yingxiu.,Zheng, Mingyue.,...&Zeng, Su.(2012).Enantioselective drug-protein interaction between mexiletine and plasma protein.JOURNAL OF PHARMACY AND PHARMACOLOGY,64(6),792-801. |
| MLA | Yu, Lushan,et al."Enantioselective drug-protein interaction between mexiletine and plasma protein".JOURNAL OF PHARMACY AND PHARMACOLOGY 64.6(2012):792-801. |
入库方式： OAI收割
来源：上海药物研究所
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