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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-Inflammatory Agents, Non-Steroidal / chemistry*
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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CD11b Antigen / chemistry
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CD11b Antigen / drug effects*
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CD11b Antigen / metabolism
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CD18 Antigens / chemistry
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CD18 Antigens / drug effects*
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CD18 Antigens / metabolism
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Caco-2 Cells
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Cell Adhesion / drug effects
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Furans / chemistry*
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Furans / pharmacology
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Humans
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Protein Conformation
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Structure-Activity Relationship
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Thiazolidinediones / chemistry*
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Thiazolidinediones / pharmacology
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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CD11b Antigen
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CD18 Antigens
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Furans
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Thiazolidinediones