Identification of novel agonists of the integrin CD11b/CD18.
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.
Faridi
Mohd Hafeez
MH
Peggy and Harold Katz Family Drug Discovery Center, Division of Nephrology and Hypertension, Department of Medicine and University of Miami, Miami, FL 33176, USA.
Maiguel
Dony
D
Barth
Constantinos J
CJ
Stoub
Darren
D
Day
Ruth
R
Schürer
Stephan
S
Gupta
Vineet
V
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
D000894:Anti-Inflammatory Agents, Non-Steroidal; D039481:CD11b Antigen; D018821:CD18 Antigens; D005663:Furans; D045162:Thiazolidinediones