Small-Molecule Disruptors of the Interaction between Calcium- and Integrin-Binding Protein 1 and Integrin αIIbβ3 as Novel Antiplatelet Agents

• DOI: 10.1021/acsptsci.4c00026
• Publication Date: 2024-05-29T13:12:45Z
• Authors: Kalyan Golla; Adam Yasgar; Voddarahally N. M...; Meghna U. Naik; Bolormaa Baljinnyam; Alexey V. Zakharov; Sankalp Jain; Ganesha Rai; Ajit Jadhav; Anton Simeonov; Ulhas P. Naik

Thrombosis, a key factor in most cardiovascular diseases, is major contributor to human mortality. Existing antithrombotic agents carry risk of bleeding. Consequently, there keen interest discovering innovative that can prevent thrombosis without negatively impacting hemostasis. Platelets play crucial roles both hemostasis and thrombosis. We have previously characterized calcium- integrin-binding protein 1 (CIB1) as regulatory molecule regulates platelet function. CIB1 interacts with several proteins including integrin αIIbβ3, the glycoprotein receptor for fibrinogen on platelets. Given function through its interaction we developed fluorescence polarization (FP) assay screen potential inhibitors. The was miniaturized 1536-well screened quantitative high-throughput screening (qHTS) format against diverse compound library 14,782 compounds. After validation selectivity testing using FP assay, identified 19 candidate inhibitors validated them an in-gel binding monitors αIIb cytoplasmic tail peptide, followed by top hits intrinsic tryptophan (ITF) microscale thermophoresis (MST) ascertain their CIB1. Two shared similar chemical structures, suggesting common mechanism action. Docking studies further revealed promising interactions within hydrophobic pocket target protein, particularly forming hydrogen bonds Ser180. compounds exhibited potent antiplatelet activity based inhibition thrombin-induced aggregation, thus indicating disruptors CIB1- αIIbβ3 could translational agents.