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题名: The conformational analysis and proton transfer of neuraminidase inhibitors: a theoretical study
作者: Yang, Zhiwei1;  Yang, Gang1;  Zu, Yuangang1;  Fu, Yujie1;  Zhou, Lijun1, 2
刊名: PHYSICAL CHEMISTRY CHEMICAL PHYSICS
发表日期: 2009
DOI: 10.1039/b909299d
卷: 11, 期:43, 页:10035-10041
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Physical Sciences
类目[WOS]: Chemistry, Physical ;  Physics, Atomic, Molecular & Chemical
研究领域[WOS]: Chemistry ;  Physics
英文摘要: With the aid of density functional calculations, it was revealed that neuraminidase (NA) inhibitors (Scheme 1) exist exclusively in the neutral form. However, the docking and molecular dynamics simulations indicated that the zwitterionic, rather than neutral, isomers are the active form in NA-receptors. The neutral and zwitterionic isomers of BA (Compound 7 in Scheme 1) are quite different in structure and is therefore expected to show distinct bioactivities. With the addition of four water molecules, the geometry of the neutral isomer (nBA4) is induced to resemble the zwitterion and remains rather stable throughout the proton transfer process (nBA4 -> zBA4); in addition, the energy difference between the zwitterionic vs. the neutral isomer is lowered from 24.76 to 2.54 kcal mol(-1). The zwitterion is the predominant isomer in aqueous solution, consistent with the conformational preference in NA-receptors. The proton transfer process of nBA4 -> zBA4 is divided into two elementary steps. Step 1, rather than step 2, plays a decisive role, owing to the larger energy barrier; however, step 1 is not assisted by solvent water, even if it is not water-suppressed. Accordingly, the proton transfer process that leads to the formation of zwitterions is not facilitated in aqueous solution, albeit they may be more stable than the neutral isomers. It is thus suggested that the designed antiviral inhibitors should be facile to transform into the zwitterionic form in aqueous solution. In this way, the oral bioavailability of the antiviral drugs can be improved.
关键词[WOS]: INFLUENZA-VIRUS NEURAMINIDASE ;  DENSITY-FUNCTIONAL THEORY ;  AMINO-ACID ZWITTERIONS ;  FREE-ENERGY ;  MOLECULAR-DYNAMICS ;  WATER CLUSTERS ;  DRUG DESIGN ;  BINDING ;  POTENT ;  SENSITIVITY
语种: 英语
WOS记录号: WOS:000271243400011
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/141319
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.NE Forestry Univ, Minist Educ, Key Lab Forest Plant Ecol, Harbin 150040, Peoples R China
2.Chinese Acad Sci, Dalian Inst Chem Phys, Dalian 116023, Peoples R China

Recommended Citation:
Yang, Zhiwei,Yang, Gang,Zu, Yuangang,et al. The conformational analysis and proton transfer of neuraminidase inhibitors: a theoretical study[J]. PHYSICAL CHEMISTRY CHEMICAL PHYSICS,2009,11(43):10035-10041.
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