Dual-Target Strategies for Cerebral Cavernous Malformations and Ischemic Stroke

Cerebral cavernous malformation (CCM) and ischemic stroke (IS) are cerebrovascular disorders characterized by endothelial dysfunction and dysregulated immune-inflammatory responses. To identify shared molecular mechanisms and therapeutic targets, we integrated gene expression profiles from GEO datasets (GSE123968, GSE130174, GSE16561), performed differential expression and WGCNA, and applied LASSO and Boruta feature selection. CD6 and IL2RB emerged as key regulators of the immune-endothelial axis, with distinct immune infiltration patterns in CCM (activated NK and CD8+ T cells) versus IS (monocytes and neutrophils). Structure-based pharmacophore models for CD6 and IL2RB were developed and used to virtually screen a CNS-focused library, followed by molecular docking, ADMET profiling, and 150 ns membrane-embedded molecular dynamics simulations. Compound 49710 exhibited high binding affinity (ΔGbind = -11.35 kcal/mol for IL2RB), conformational stability (RMSD ≤ 0.6 nm; Rg ≤ 2.2 nm2; SASA ≤ 122 nm2), and favorable pharmacokinetics, identifying it as a potential lead compound, This integrative multi-omics and computational approach provides a framework for precision therapeutics targeting convergent mechanisms in complex vascular diseases.