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<p>Calcium- and integrin-binding protein 1 (CIB1) regulates integrin αIIbβ3 signaling through its interaction with the αIIb cytoplasmic tail, making the CIB1–αIIb interface a potential target for modulating platelet activation and thrombus stabilization. In this study, we applied an integrated computational and experimental workflow to identify small-molecule disruptors of the CIB1–αIIb interaction. A focused library of benzimidazole-2-carboxamide derivatives was virtually screened against the Ca²⁺-bound CIB1 structure using drug-likeness filtering, AutoDock Vina docking, short molecular dynamics refinement, diversity and purchasability selection, and MM/PBSA rescoring. Three candidates, designated Compound 1, Compound 2, and Compound 3, were selected for further evaluation alongside the reference disruptor NCGC00071855. Long-timescale 1000 ns molecular dynamics simulations showed that the selected compounds maintained more stable CIB1 engagement than the reference compound, with Compound 1 showing the most persistent pocket retention and residue-level proximity to key binding-site residues. MM/PBSA calculations identified Compound 2 as the most energetically favorable binder, with a ΔG<sub>TOTAL</sub> of − 32.85 ± 12.38&#xa0;kcal/mol. In silico ADMET profiling suggested that Compound 1 and Compound 3 had more favorable drug-likeness profiles than Compound 2, although all candidates showed liabilities requiring further optimization. Experimental fluorescence polarization assays confirmed concentration-dependent disruption of the CIB1–αIIb interaction, with IC₅₀ values of 6.32 ± 0.23 µM, 3.70 ± 0.05 µM, and 4.79 ± 0.08 µM for Compounds 1–3, respectively, compared with 17.44 ± 0.87 µM for NCGC00071855. These findings establish benzimidazole-2-carboxamide derivatives as promising starting points for developing CIB1–αIIb interaction modulators.</p>

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Benzimidazole-2-carboxamide derivatives as small-molecule modulators of the thrombosis-related CIB1–integrin αIIb protein–protein interaction: computational and experimental insights

  • 期刊论文

  • 发表日期：

    2026年6月29日

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  • Emadeldin M. Kamel,
  • Ahmed A. Allam,
  • Raghad A. Alotaibi,
  • May Bin-Jumah,
  • Fahad M. Alshabrmi,
  • Faris F. Aba Alkhayl,
  • Al Mokhtar Lamsabhi

摘要

Calcium- and integrin-binding protein 1 (CIB1) regulates integrin αIIbβ3 signaling through its interaction with the αIIb cytoplasmic tail, making the CIB1–αIIb interface a potential target for modulating platelet activation and thrombus stabilization. In this study, we applied an integrated computational and experimental workflow to identify small-molecule disruptors of the CIB1–αIIb interaction. A focused library of benzimidazole-2-carboxamide derivatives was virtually screened against the Ca²⁺-bound CIB1 structure using drug-likeness filtering, AutoDock Vina docking, short molecular dynamics refinement, diversity and purchasability selection, and MM/PBSA rescoring. Three candidates, designated Compound 1, Compound 2, and Compound 3, were selected for further evaluation alongside the reference disruptor NCGC00071855. Long-timescale 1000 ns molecular dynamics simulations showed that the selected compounds maintained more stable CIB1 engagement than the reference compound, with Compound 1 showing the most persistent pocket retention and residue-level proximity to key binding-site residues. MM/PBSA calculations identified Compound 2 as the most energetically favorable binder, with a ΔGTOTAL of − 32.85 ± 12.38 kcal/mol. In silico ADMET profiling suggested that Compound 1 and Compound 3 had more favorable drug-likeness profiles than Compound 2, although all candidates showed liabilities requiring further optimization. Experimental fluorescence polarization assays confirmed concentration-dependent disruption of the CIB1–αIIb interaction, with IC₅₀ values of 6.32 ± 0.23 µM, 3.70 ± 0.05 µM, and 4.79 ± 0.08 µM for Compounds 1–3, respectively, compared with 17.44 ± 0.87 µM for NCGC00071855. These findings establish benzimidazole-2-carboxamide derivatives as promising starting points for developing CIB1–αIIb interaction modulators.