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题名: Selectivity of Neutral/Weakly Basic P1 Group Inhibitors of Thrombin and Trypsin by a Molecular Dynamics Study
作者: Wu, Emilia L.1;  Han, KeLi1;  Zhang, John Z. H.2, 3
关键词: molecular dynamics ;  molecular mechanics ;  selectivity ;  thrombin ;  trypsin
刊名: CHEMISTRY-A EUROPEAN JOURNAL
发表日期: 2008
DOI: 10.1002/chem.200800277
卷: 14, 期:28, 页:8704-8714
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Physical Sciences
类目[WOS]: Chemistry, Multidisciplinary
研究领域[WOS]: Chemistry
英文摘要: Molecular dynamics (MD) simulations followed by molecular mechanics generalized Born surface area (MM-GBSA) analyses have been carried out to study the selectivity of two neutral and weakly basic P1 group inhibitors (177 and CDA) to thrombin and trypsin. Detailed binding free energies between these inhibitors and individual protein residues are calculated by using a per-residue basis decomposition method. The analysis of the detailed interaction energies provides in-sight on the protein-inhibitor-binding mechanism and helps to elucidate the basis for achieving selectivity through interpretation of the structural and energetic results from the simulations. The study shows that the dominant factor of selectivity for both inhibitors is van der Waals energy, which suggests better shape complementarity and packing with thrombin. Nonpolar solvation free energy and total entropy contribution are also in favor of selectivity, but the contributions are much smaller. Binding mode and structural analysis show that 177 binds to thrombin and trypsin in a similar binding mode. In contrast, the CDA binds to thrombin and trypsin in very different modes.
关键词[WOS]: SERINE-PROTEASE INHIBITORS ;  ORALLY BIOAVAILABLE SERIES ;  FREE-ENERGY DECOMPOSITION ;  STRUCTURE-BASED DESIGN ;  BINDING FREE-ENERGIES ;  HUMAN ALPHA-THROMBIN ;  CRYSTAL-STRUCTURE ;  FACTOR XA ;  PLASMINOGEN-ACTIVATOR ;  RESP MODEL
语种: 英语
WOS记录号: WOS:000260035900033
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/140785
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.Chinese Acad Sci, Dalian Inst Chem Phys, State Key Lab Mol React Dynam, Dalian 116023, Peoples R China
2.Nanjing Univ, Inst Theoret & Computat Chem, Sch Chem & Chem Engn, Nanjing 210093, Peoples R China
3.NYU, Dept Chem, New York, NY 10003 USA

Recommended Citation:
Wu, Emilia L.,Han, KeLi,Zhang, John Z. H.. Selectivity of Neutral/Weakly Basic P1 Group Inhibitors of Thrombin and Trypsin by a Molecular Dynamics Study[J]. CHEMISTRY-A EUROPEAN JOURNAL,2008,14(28):8704-8714.
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