Identification of novel agonists of the integrin CD11b/CD18

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

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 languageEnglish
Pages (from-to)6902-6906
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume19
Issue number24
DOIs
StatePublished - Dec 15 2009

Fingerprint

Integrins
Complement C3b
Ligands
Computer Simulation
Fibrinogen
Adhesion
Modulation
Molecules
Experiments
In Vitro Techniques

Keywords

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

ASJC Scopus subject areas

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

Cite this

Identification of novel agonists of the integrin CD11b/CD18. / Faridi, Mohd Hafeez; Maiguel, Dony; Barth, Constantinos J.; Stoub, Darren; Day, Ruth; Schuerer, Stephan C; Gupta, Vineet.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 19, No. 24, 15.12.2009, p. 6902-6906.

Research output: Contribution to journalArticle

Faridi, MH, Maiguel, D, Barth, CJ, Stoub, D, Day, R, Schuerer, SC & Gupta, V 2009, 'Identification of novel agonists of the integrin CD11b/CD18', Bioorganic and Medicinal Chemistry Letters, vol. 19, no. 24, pp. 6902-6906. https://doi.org/10.1016/j.bmcl.2009.10.077
Faridi, Mohd Hafeez ; Maiguel, Dony ; Barth, Constantinos J. ; Stoub, Darren ; Day, Ruth ; Schuerer, Stephan C ; Gupta, Vineet. / Identification of novel agonists of the integrin CD11b/CD18. In: Bioorganic and Medicinal Chemistry Letters. 2009 ; Vol. 19, No. 24. pp. 6902-6906.
@article{b6ed5aabca0a4228b1b13055f81a803f,
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 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.",
keywords = "Agonist, CD11b/CD18, Cell-adhesion, Cell-based assay, High-throughput screening, Inflammation, Integrin, Mac-1",
author = "Faridi, {Mohd Hafeez} and Dony Maiguel and Barth, {Constantinos J.} and Darren Stoub and Ruth Day and Schuerer, {Stephan C} and Vineet Gupta",
year = "2009",
month = "12",
day = "15",
doi = "10.1016/j.bmcl.2009.10.077",
language = "English",
volume = "19",
pages = "6902--6906",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "24",

}

TY - JOUR

T1 - Identification of novel agonists of the integrin CD11b/CD18

AU - Faridi, Mohd Hafeez

AU - Maiguel, Dony

AU - Barth, Constantinos J.

AU - Stoub, Darren

AU - Day, Ruth

AU - Schuerer, Stephan C

AU - Gupta, Vineet

PY - 2009/12/15

Y1 - 2009/12/15

N2 - 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.

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

UR - http://www.scopus.com/inward/record.url?scp=71849103682&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=71849103682&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2009.10.077

DO - 10.1016/j.bmcl.2009.10.077

M3 - Article

VL - 19

SP - 6902

EP - 6906

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 24

ER -