Virtual screening leads to the discovery of an effective antagonist of lymphocyte function-associated antigen-1.
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 approximately 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.
Shoda
Miyuki
M
Laboratory For Drug Discovery, Research Center, Pharmaceutical R&D Division, Asahi KASEI Pharma Corporation, 632-1 Mifuku, Izunokuni-shi, Shizuoka, Japan.
Harada
Takeo
T
Yano
Kazuo
K
Stahura
Florence L
FL
Himeno
Takeshi
T
Shiojiri
Satoshi
S
Kogami
Yuji
Y
Kouji
Hiroyuki
H
Bajorath
Jürgen
J
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology*; D019295:Computational Biology; D003198:Computer Simulation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1