Structure-based virtual screening of small-molecule antagonists of platelet integrin ?IIb?3 that do not prime the receptor to bind ligand.

ABSTRACT: Integrin ?IIb?3 has emerged as an important therapeutic target for thrombotic vascular diseases owing to its pivotal role in mediating platelet aggregation through interaction with adhesive ligands. In the search for effective anti-thrombotic agents that can be administered orally without inducing the high-affinity ligand binding state, we recently discovered via high-throughput screening of 33,264 compounds a novel, ?IIb?3-selective inhibitor (RUC-1) of adenosine-5'-diphosphate (ADP) -induced platelet aggregation that exhibits a different chemical scaffold and mode of binding with respect to classical Arg-Gly-Asp (RGD)-mimicking ?IIb?3 antagonists. Most importantly, RUC-1 and its higher-affinity derivative, RUC-2, do not induce major conformational changes in the protein ?3 subunit or prime the receptor to bind ligand. To identify additional ?IIb?3-selective chemotypes that inhibit platelet aggregation through similar mechanisms, we screened in silico over 2.5 million commercially available, 'lead-like' small molecules based on complementarity to the predicted binding mode of RUC-2 into the RUC-1-?IIb?3 crystal structure. This first reported structure-based virtual screening application to the ?IIb?3 integrin led to the identification of 2 ?IIb?3-selective antagonists out of 4 tested, which compares favorably with the 0.003 % "hit rate" of our previous high-throughput chemical screening study. The newly identified compounds, like RUC-1 and RUC-2, showed specificity for ?IIb?3 compared to ?V?3 and did not prime the receptor to bind ligand. They thus may hold promise as ?IIb?3 antagonist therapeutic scaffolds.

SUBMITTER: Negri A 

PROVIDER: S-EPMC3496400 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature