title: Identification of novel agonists of the integrin CD11b/CD18.
abstract: We report the identification of novel small molecule agonists of integrin CD11b/CD18, which increased, in a dose-dependent manner, the adhesion of the integrin CD11b/CD18 expressing cells to two physiologically relevant ligands: Fibrinogen and iC3b. Compound 6 showed an ex vivo EC(50) of 10.5 microM and in vitro selectivity for binding to the recombinant alphaA-domain of CD11b/CD18. In silico docking experiments suggest that the compounds recognized a hydrophobic cleft in the ligand-binding alphaA-domain, implying an allosteric mechanism of modulation of integrin affinity by this novel compound.
authors.affiliation: Peggy and Harold Katz Family Drug Discovery Center, Division of Nephrology and Hypertension, Department of Medicine and University of Miami, Miami, FL 33176, USA.
authors.forename: Mohd Hafeez
authors.initials: MH
authors.lastname: Faridi
authors.forename: Dony
authors.initials: D
authors.lastname: Maiguel
authors.forename: Constantinos J
authors.initials: CJ
authors.lastname: Barth
authors.forename: Darren
authors.initials: D
authors.lastname: Stoub
authors.forename: Ruth
authors.initials: R
authors.lastname: Day
authors.forename: Stephan
authors.initials: S
authors.lastname: Schürer
authors.forename: Vineet
authors.initials: V
authors.lastname: Gupta
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology; D039481:CD11b Antigen / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D018821:CD18 Antigens / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D018938:Caco-2 Cells; D002448:Cell Adhesion / Q000187:drug effects; D005663:Furans / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D039481:CD11b Antigen; D018821:CD18 Antigens; D005663:Furans; D045162:Thiazolidinediones