title: Virtual screening leads to the discovery of an effective antagonist of lymphocyte function-associated antigen-1.
abstract: 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.
authors.affiliation: Laboratory For Drug Discovery, Research Center, Pharmaceutical R&D Division, Asahi KASEI Pharma Corporation, 632-1 Mifuku, Izunokuni-shi, Shizuoka, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Shoda
authors.forename: Takeo
authors.initials: T
authors.lastname: Harada
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yano
authors.forename: Florence L
authors.initials: FL
authors.lastname: Stahura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Himeno
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shiojiri
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kogami
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kouji
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bajorath
mesh_terms: 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
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1