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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. This Article Full Text (PDF) Supplemental Videos All Versions of this Article: blood-2007-08-105544v1 111/3/1248    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Blue, R. Articles by Coller, B. S. Search for Related Content PubMed PubMed Citation Articles by Blue, R. Articles by Coller, B. S. Social Bookmarking                   What's this?  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 IIb3-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 IIb3 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 IIb3 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 IIb3. Compound 1 did not affect the function of GPIb, 21, or the other 3 family receptor V3. 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 IIb3 to eptifibatide, but not compound 1, enhanced fibrinogen binding ("priming"). Compound 1 provides a prototype for small molecule selective inhibition of IIb3, 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]

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