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学科主题: 药学
题名:
Identification of Small-Molecule Inhibitors against Human Leukocyte Antigen-Death Receptor 4 (HLA-DR4) Through a Comprehensive Strategy
作者: Liu, Zhenming1,2; Li, Bo2; Li, Xia3; Zhang, Liangren1; Lai, Luhua2
刊名: JOURNAL OF CHEMICAL INFORMATION AND MODELING
发表日期: 2011-02-01
DOI: 10.1021/ci100444c
卷: 51, 期:2, 页:326-334
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Chemistry, Medicinal ; Chemistry, Multidisciplinary ; Computer Science, Information Systems ; Computer Science, Interdisciplinary Applications
研究领域[WOS]: Pharmacology & Pharmacy ; Chemistry ; Computer Science
关键词[WOS]: ALTERED PEPTIDE LIGAND ; T-CELL-ACTIVATION ; HEMAGGLUTININ-DERIVED PEPTIDES ; COLLAGEN-INDUCED ARTHRITIS ; RHEUMATOID-ARTHRITIS ; INFLUENZA-VIRUS ; II COLLAGEN ; AUTOIMMUNE ARTHRITIS ; AUTOMATED DOCKING ; 3D DATABASE
英文摘要:

Rheumatoid arthritis (RA) is an autoimmune disease mediated by T-lymphocytes and associated with the human leukocyte antigen-death receptor 4 (HLA-DR4). The HLA-DR4 protein selectively interacts with the antigenic peptides on the cell surface and presents them to the T cell receptor (TCR) on CD4+ T cells. The 1-ILA-DR4-antigen-TCR complex initiates the autoimmune response and eventually causes the chronic inflammation within patients bodies. To inhibit HLA-DR4-restricted T cell activation, an ideal approach is to discover non-T cell stimulating substrates that specifically bind to HLA-DR4. In this paper, a comprehensive structure-based design strategy involved de novo design approach, pharmacophore search, and dock method was presented and applied to "simplify" the known binding peptide ligand of HLA-DR4 and identified specific small-molecule inhibitors for HLA-DR4. The designed three-step strategy successfully identified five nonpeptide ligands with novel scaffolds from a chemical library containing 4 x 10(6) commercially available compounds within a tolerable computing time. The identified five chemicals, BAS-0219606, T0506-2494, 6436645, 3S-71981, and KM 11073, are all non-T cell stimulators and are able to significantly inhibit HLA-DR4-restricted T cell activation induced by type II collagen (CH) 263-272 peptide. IC50 for the best two potentials, BAS-0219606 and T0506-2494, was 31 and 17 mu M, respectively, which is equivalent or better than the known peptide ligands. It is hopeful that they can be used as effective therapeutic means for further treatment of RA patients. In addition, the comprehensive strategy presented in this paper exhibited itself to be an effective flow line from peptide ligands to small-molecule inhibitors and will have applications to other targets.

语种: 英语
所属项目编号: 2009ZX09501-002 ; 20802006
项目资助者: Major National S&amp ; T Program "Key Drug Scheme Funds" ; National Natural Science Foundation of China
WOS记录号: WOS:000287685700014
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/65086
Appears in Collections:北京大学药学院_期刊论文

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作者单位: 1.Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100871, Peoples R China
2.Peking Univ, Coll Chem & Mol Engn, State Key Lab Struct Chem Unstable & Stable Speci, Beijing 100871, Peoples R China
3.Nanjing Univ, Nanjing Drum Tower Hosp, Sch Med, Dept Rheumatol & Immunol, Nanjing 210008, Peoples R China

Recommended Citation:
Liu, Zhenming,Li, Bo,Li, Xia,et al. Identification of Small-Molecule Inhibitors against Human Leukocyte Antigen-Death Receptor 4 (HLA-DR4) Through a Comprehensive Strategy[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING,2011,51(2):326-334.
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