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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

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Structure-based virtual screening of small-molecule antagonists of platelet integrin αIIbβ3 that do not prime the receptor to bind ligand.

Negri Ana A Li Jihong J Naini Sarasija S Coller Barry S BS Filizola Marta M

Journal of computer-aided molecular design 20120815 9

Integrin αIIbβ3 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, αIIbβ3-selective inhibitor (RUC-1) of adenosine-5'-diphosphate (ADP) -induced p ...[more]

PMID: 22893377

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Project description:The major platelet integrin, glycoprotein IIb-IIIa, binds soluble fibrinogen only after platelet activation. To investigate the mechanism by which platelets convert glycoprotein IIb-IIIa into a functional fibrinogen receptor, we characterized the opening and closing of fibrinogen-binding sites in isolated platelet membranes and compared the regulatory properties of membrane-bound glycoprotein IIb-IIIa with those of the detergent-solubilized receptor. Basal fibrinogen binding to the membranes possessed many of the properties of fibrinogen binding to activated platelets; however, less than 10% of glycoprotein IIb-IIIa in the membranes was capable of binding fibrinogen. Preincubating the membranes with either an activating glycoprotein IIb-IIIa antibody or alpha-chymotrypsin increased fibrinogen binding. In contrast, agents that require intracellular mediators, such as platelet agonists, guanine-nucleotide-binding-protein activators and purified protein kinase C, did not stimulate fibrinogen binding to the membranes, suggesting that cytosolic factor(s) may be required for activation of the receptor in platelets. Occupancy of glycoprotein IIb-IIIa in the membranes with RGD (Arg-Gly-Asp)-containing peptides reversibly exposed neoantigenic epitopes and fibrinogen-binding sites in the receptor. These conformational changes required membrane fixation to be maintained following peptide removal. Similar results were obtained with purified glycoprotein IIb-IIIa incorporated into phospholipid vesicles, indicating that the resting state of the receptor is favoured in these environments. In contrast, when the conformation of detergent-solubilized glycoprotein IIb-IIIa was altered by exposure to RGD-containing peptides, the receptor remained active even after incorporation into phospholipid vesicles. These results demonstrate that platelet membranes are a useful model in which to study the regulation of glycoprotein IIb-IIIa and suggest that the environment surrounding the receptor may have a profound influence on this process.

Dataset Information

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

Publications

Structure-based virtual screening of small-molecule antagonists of platelet integrin αIIbβ3 that do not prime the receptor to bind ligand.

Similar Datasets

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