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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.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Application of high-throughput screening to identify a novel  IIb-specific small- molecule inhibitor of IIbβ3-mediated platelet interaction with fibrinogen
Robert Blue1,
Marta Murcia2,
Charles Karan3,
Markéta Jirou ková1, and
Barry S. Coller1
1 Laboratory of Blood and Vascular Biology, The Rockefeller University, New York, NY;
2 Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY; and
3 High Throughput Screening Resource Center, The Rockefeller University, New York, NY
Small-molecule  IIbβ3 antagonists competitively block ligand binding by spanning between the D224 in IIb and the MIDAS metal ion in β3. They variably induce conformational changes in the receptor, which may have undesirable consequences. To identify IIbβ3 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% or more 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 IIbβ3. Compound 1 did not affect the function of GPIb, 2β1, or the other β3 family receptor Vβ3. Molecular docking simulations suggest that compound 1 interacts with IIb but not β3. Compound 1 induced partial exposure of an IIb ligand-induced binding site (LIBS), but did not induce exposure of 2 β3 LIBS. Transient exposure of purified IIbβ3 to eptifibatide, but not compound 1, enhanced fibrinogen binding ("priming"). Compound 1 provides a prototype for small molecule selective inhibition of IIbβ3, without receptor priming, via targeting IIb.
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