|
|
Blood, 1 February 2008, Vol. 111, No. 3, pp. 1248-1256.
Prepublished online as a Blood First Edition Paper on October 31, 2007; DOI 10.1182/blood-2007-08-105544.
Previous Article | Next Article 
Submitted August 6, 2007
Accepted October 24, 2007
Application of high throughput screening to identify a novel IIb-specific small molecule inhibitor of IIb 3-mediated platelet interaction with fibrinogen
Robert Blue, Marta Murcia, Charles Karan, Marketa Jirouskova, and Barry S. Coller*
Laboratory of Blood and Vascular Biology, Rockefeller University, New York, NY
Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY
High Throughput Screening Resource Center, Rockefeller University, New York, NY
* Corresponding author; email: collerb{at}rockefeller.edu.
Small molecule IIb 3 antagonists competitively block ligand binding by spanning between the D224 in IIb and the MIDAS metal ion in 3. They variably induce conformational changes in the receptor, which may have undesirable consequences. To identify IIb 3 antagonists with novel structures, we tested 33,264 small molecules for their ability to inhibit the adhesion of washed platelets to immobilized fibrinogen at 16 µM. A total of 102 compounds demonstrated 50% inhibition, and one of these (compound 1, 265 g/mol) inhibited ADP-induced platelet aggregation (IC50 13 ± 5 µM), the binding of soluble fibrinogen to platelets induced by mAb AP5, and the binding of soluble fibrinogen and a cyclic RGD peptide to purified IIb 3. Compound 1 did not affect the function of GPIb, 2 1, or the other 3 family receptor V 3. Molecular docking simulations suggest that compound 1 interacts with IIb, but not 3. Compound 1 induced partial exposure of an IIb ligand induced binding site (LIBS), but did not induce exposure of 2 3 LIBS. Transient exposure of purified IIb 3 to eptifibatide, but not compound 1, enhanced fibrinogen binding ("priming"). Compound 1 provides a prototype for small molecule selective inhibition of IIb 3, without receptor priming, via targeting IIb.

CiteULike Connotea Del.icio.us Digg Reddit Technorati What's this?
This article has been cited by other articles:

|
 |

|
 |
 
R. Blue, M. A. Kowalska, J. Hirsch, M. Murcia, C. A. Janczak, A. Harrington, M. Jirouskova, J. Li, R. Fuentes, M. A. Thornton, et al.
Structural and therapeutic insights from the species specificity and in vivo antithrombotic activity of a novel {alpha}IIb-specific {alpha}IIb{beta}3 antagonist
Blood,
July 2, 2009;
114(1):
195 - 201.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
Z. Pamuklar, L. Federico, S. Liu, M. Umezu-Goto, A. Dong, M. Panchatcharam, Z. Fulerson, E. Berdyshev, V. Natarajan, X. Fang, et al.
Autotaxin/Lysopholipase D and Lysophosphatidic Acid Regulate Murine Hemostasis and Thrombosis
J. Biol. Chem.,
March 13, 2009;
284(11):
7385 - 7394.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
B. S. Coller and S. J. Shattil
The GPIIb/IIIa (integrin {alpha}IIb{beta}3) odyssey: a technology-driven saga of a receptor with twists, turns, and even a bend
Blood,
October 15, 2008;
112(8):
3011 - 3025.
[Abstract]
[Full Text]
[PDF]
|
 |
|
|
|