Identification of novel agonists of the integrin CD11b/CD18

Mohd Hafeez Faridi; Dony Maiguel; Constantinos J. Barth; Darren Stoub; Ruth Day; Stephan Schürer; Vineet Gupta

doi:10.1016/j.bmcl.2009.10.077

Identification of novel agonists of the integrin CD11b/CD18

Mohd Hafeez Faridi, Dony Maiguel, Constantinos J. Barth, Darren Stoub, Ruth Day, Stephan Schürer, Vineet Gupta

Research output: Contribution to journal › Article › peer-review

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 EC₅₀ of 10.5 μM and in vitro selectivity for binding to the recombinant αA-domain of CD11b/CD18. In silico docking experiments suggest that the compounds recognized a hydrophobic cleft in the ligand-binding αA-domain, implying an allosteric mechanism of modulation of integrin affinity by this novel compound.

Original language	English (US)
Pages (from-to)	6902-6906
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	19
Issue number	24
DOIs	https://doi.org/10.1016/j.bmcl.2009.10.077
State	Published - Dec 15 2009
Externally published	Yes

Keywords

Agonist
CD11b/CD18
Cell-adhesion
Cell-based assay
High-throughput screening
Inflammation
Integrin
Mac-1

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2009.10.077

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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 EC50 of 10.5 μM and in vitro selectivity for binding to the recombinant αA-domain of CD11b/CD18. In silico docking experiments suggest that the compounds recognized a hydrophobic cleft in the ligand-binding αA-domain, implying an allosteric mechanism of modulation of integrin affinity by this novel compound.",

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doi = "10.1016/j.bmcl.2009.10.077",

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AU - Faridi, Mohd Hafeez

AU - Maiguel, Dony

AU - Barth, Constantinos J.

AU - Stoub, Darren

AU - Day, Ruth

AU - Schürer, Stephan

AU - Gupta, Vineet

PY - 2009/12/15

Y1 - 2009/12/15

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AB - 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 EC50 of 10.5 μM and in vitro selectivity for binding to the recombinant αA-domain of CD11b/CD18. In silico docking experiments suggest that the compounds recognized a hydrophobic cleft in the ligand-binding αA-domain, implying an allosteric mechanism of modulation of integrin affinity by this novel compound.

KW - Agonist

KW - CD11b/CD18

KW - Cell-adhesion

KW - Cell-based assay

KW - High-throughput screening

KW - Inflammation

KW - Integrin

KW - Mac-1

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Identification of novel agonists of the integrin CD11b/CD18

Abstract

Keywords

ASJC Scopus subject areas

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