title: High-throughput screening based identification of small molecule antagonists of integrin CD11b/CD18 ligand binding.
abstract: Binding of leukocyte specific integrin CD11b/CD18 to its physiologic ligands is important for the development of normal immune response in vivo. Integrin CD11b/CD18 is also a key cellular effector of various inflammatory and autoimmune diseases. However, small molecules selectively inhibiting the function of integrin CD11b/CD18 are currently lacking. We used a newly described cell-based high-throughput screening assay to identify a number of highly potent antagonists of integrin CD11b/CD18 from chemical libraries containing >100,000 unique compounds. Computational analyses suggest that the identified compounds cluster into several different chemical classes. A number of the newly identified compounds blocked adhesion of wild-type mouse neutrophils to CD11b/CD18 ligand fibrinogen. Mapping the most active compounds against chemical fingerprints of known antagonists of related integrin CD11a/CD18 shows little structural similarity, suggesting that the newly identified compounds are novel and unique.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Peggy and Harold Katz Family Drug Discovery Center, Miami, FL 33136, USA.
authors.forename: Mohd Hafeez
authors.initials: MH
authors.lastname: Faridi
authors.forename: Dony
authors.initials: D
authors.lastname: Maiguel
authors.forename: Brock T
authors.initials: BT
authors.lastname: Brown
authors.forename: Eigo
authors.initials: E
authors.lastname: Suyama
authors.forename: Constantinos J
authors.initials: CJ
authors.lastname: Barth
authors.forename: Michael
authors.initials: M
authors.lastname: Hedrick
authors.forename: Stefan
authors.initials: S
authors.lastname: Vasile
authors.forename: Eduard
authors.initials: E
authors.lastname: Sergienko
authors.forename: Stephan
authors.initials: S
authors.lastname: Schürer
authors.forename: Vineet
authors.initials: V
authors.lastname: Gupta
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism*; D018821:CD18 Antigens / Q000378:metabolism*; D057166:High-Throughput Screening Assays; D008024:Ligands; D051379:Mice; D008815:Mice, Inbred Strains; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D054852:Small Molecule Libraries
chemical_list: D039481:CD11b Antigen; D018821:CD18 Antigens; D008024:Ligands; D054852:Small Molecule Libraries