PMID- 15456243
OWN - NLM
STAT- MEDLINE
DCOM- 20041110
LR  - 20121115
IS  - 0022-2623 (Print)
IS  - 0022-2623 (Linking)
VI  - 47
IP  - 21
DP  - 2004 Oct 7
TI  - Structure-based discovery of nonpeptidic small organic compounds to block the T 
      cell response to myelin basic protein.
PG  - 4989-97
AB  - We have utilized a computational structure-based approach to identify nonpeptidic 
      small organic compounds that bind to a human leukocyte antigen (HLA) DR1301 
      molecule (HLA-DR1301 or DR1301) and block the presentation of myelin basic 
      protein peptide 152-165 (MBP 152-165) to T cells. A three-dimensional (3D) 
      structure of DR1301 was derived by homology modeling followed by extensive 
      molecular dynamics simulation for structural refinement. Computational 
      structure-based database searching was performed to identify nonpeptidic 
      small-molecule candidates from the National Cancer Institute (NCI) database 
      containing over 150 000 compounds that can effectively interact with the 
      peptide-binding groove of the HLA molecule. By in vitro testing of 106 candidate 
      small molecules, two lead compounds were confirmed to specifically block IL-2 
      secretion by DR1301-restricted T cells in a dose-dependent and reversible manner. 
      The specificity of blocking DR1301-restricted MBP presentation was further 
      validated in a binding assay using an analogue of the most potent lead compound. 
      Computational docking was performed to predict the three-dimensional binding 
      model of these confirmed small molecule blockers to the DR1301 molecule and to 
      gain structural insight into their interactions. Our results suggest that 
      computational structure-based searching is an effective approach to discover 
      nonpeptidic small organic compounds to block the interaction between DR1301 and T 
      cells. The nonpeptidic small organic compounds identified in this study are 
      useful pharmacological tools to study the interactions between HLA molecules and 
      T cells and a starting point for the development of a novel therapeutic strategy 
      for the treatment of multiple sclerosis (MS) or other immune-related disorders.
FAU - Koehler, Niklas K U
AU  - Koehler NK
AD  - Departments of Microbiology and Immunology, Neurology, and Pathology, Georgetown 
      University Medical Center, Washington, D.C. 20007, USA.
FAU - Yang, Chao-Yie
AU  - Yang CY
FAU - Varady, Judith
AU  - Varady J
FAU - Lu, Yipin
AU  - Lu Y
FAU - Wu, Xiong-Wu
AU  - Wu XW
FAU - Liu, Ming
AU  - Liu M
FAU - Yin, Daxu
AU  - Yin D
FAU - Bartels, Margreet
AU  - Bartels M
FAU - Xu, Bi-ying
AU  - Xu BY
FAU - Roller, Peter P
AU  - Roller PP
FAU - Long, Ya-qiu
AU  - Long YQ
FAU - Li, Peng
AU  - Li P
FAU - Kattah, Michael
AU  - Kattah M
FAU - Cohn, Marjorie L
AU  - Cohn ML
FAU - Moran, Kelly
AU  - Moran K
FAU - Tilley, Eurona
AU  - Tilley E
FAU - Richert, John R
AU  - Richert JR
FAU - Wang, Shaomeng
AU  - Wang S
LA  - eng
GR  - P30 CA 51008/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Azo Compounds)
RN  - 0 (HLA-DR Antigens)
RN  - 0 (HLA-DRB1 Chains)
RN  - 0 (HLA-DRB1*13:01 antigen)
RN  - 0 (HLA-DRB1*15:01 antigen)
RN  - 0 (Interleukin-2)
RN  - 0 (Myelin Basic Protein)
RN  - 0 (Naphthalenes)
RN  - 0 (Peptide Fragments)
RN  - 0 (Quinoxalines)
RN  - 0 (myelin basic protein 152-165)
SB  - IM
MH  - Animals
MH  - Azo Compounds/chemistry/*pharmacology
MH  - Binding Sites
MH  - Binding, Competitive
MH  - Cell Line
MH  - Databases, Factual
MH  - HLA-DR Antigens/chemistry/*immunology
MH  - HLA-DRB1 Chains
MH  - Humans
MH  - Interleukin-2/biosynthesis
MH  - Mice
MH  - Models, Molecular
MH  - Myelin Basic Protein/chemistry/*immunology
MH  - Naphthalenes/chemistry/*pharmacology
MH  - Peptide Fragments/chemistry/*immunology
MH  - Quinoxalines/chemistry/*pharmacology
MH  - Structure-Activity Relationship
MH  - T-Lymphocytes/*drug effects/immunology
EDAT- 2004/10/01 05:00
MHDA- 2004/11/13 09:00
CRDT- 2004/10/01 05:00
PHST- 2004/10/01 05:00 [pubmed]
PHST- 2004/11/13 09:00 [medline]
PHST- 2004/10/01 05:00 [entrez]
AID - 10.1021/jm030362s [doi]
PST - ppublish
SO  - J Med Chem. 2004 Oct 7;47(21):4989-97. doi: 10.1021/jm030362s.