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Virtual Screening Leads to the Discovery of an Effective Antagonist of Lymphocyte Function‐Associated Antigen‐1
Author(s) -
Shoda Miyuki,
Harada Takeo,
Yano Kazuo,
Stahura Florence L.,
Himeno Takeshi,
Shiojiri Satoshi,
Kogami Yuji,
Kouji Hiroyuki,
Bajorath Jürgen
Publication year - 2007
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200600288
Subject(s) - virtual screening , lymphocyte function associated antigen 1 , lymphocyte , ligand (biochemistry) , antagonist , cell adhesion , antigen , intracellular , function (biology) , microbiology and biotechnology , adhesion , t lymphocyte , icam 1 , intercellular adhesion molecule 1 , cell adhesion molecule , intercellular adhesion molecule , chemistry , computational biology , cell , biology , receptor , immunology , biochemistry , drug discovery , organic chemistry
The binding of lymphocyte function‐associated antigen‐1 (LFA‐1) to its ligand on endothelial cells, intercellular adhesion molecule‐1 (ICAM‐1), is a crucial step in the migration of leukocytes during the early stages of inflammation and is also involved in T‐cell activation. In this paper, we report the identification of a series of novel antagonists of the LFA‐1/ICAM‐1 interaction using ligand‐based virtual screening (VS), analogue design, and structure–activity relationship (SAR) analysis. Candidate compounds were evaluated in protein binding and cell adhesion assays. Experimental evaluation of only 25 candidates selected from a pool of ∼2.5 million database compounds identified an initial hit that could be expanded and converted into a lead that effectively blocked the interaction between LFA‐1 and ICAM‐1.