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Identification of Small-Molecule Inhibitors against Human Leukocyte Antigen-Death Receptor 4 (HLA-DR4) Through a Comprehensive Strategy
Liu, Zhenming1,2; Li, Bo2; Li, Xia3; Zhang, Liangren1; Lai, Luhua2
2011-02-01
Source PublicationJOURNAL OF CHEMICAL INFORMATION AND MODELING
ISSN1549-9596
Volume51Issue:2Pages:326-334
AbstractRheumatoid 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.
DOI10.1021/ci100444c
Indexed BySCI
Language英语
WOS IDWOS:000287685700014
PublisherAMER CHEMICAL SOC
Citation statistics
Cited Times:10[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.iccas.ac.cn/handle/121111/73730
Collection中国科学院化学研究所
Corresponding AuthorLiu, Zhenming
Affiliation1.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
GB/T 7714
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.
APA Liu, Zhenming,Li, Bo,Li, Xia,Zhang, Liangren,&Lai, Luhua.(2011).Identification of Small-Molecule Inhibitors against Human Leukocyte Antigen-Death Receptor 4 (HLA-DR4) Through a Comprehensive Strategy.JOURNAL OF CHEMICAL INFORMATION AND MODELING,51(2),326-334.
MLA Liu, Zhenming,et al."Identification of Small-Molecule Inhibitors against Human Leukocyte Antigen-Death Receptor 4 (HLA-DR4) Through a Comprehensive Strategy".JOURNAL OF CHEMICAL INFORMATION AND MODELING 51.2(2011):326-334.
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