Structure-based drug repurposing and in vitro evaluation of VAV2-associated candidates for suppression of macrophage foam-cell formation in atherosclerosis.

Cardiovascular disease remains a leading cause of mortality worldwide, and macrophage-derived foam-cell formation represents an important event in atherosclerosis. VAV2, a Rho-family guanine nucleotide-exchange factor, participates in signalling pathways associated with oxidized low-density lipoprotein uptake and macrophage lipid accumulation. In this study, a structure-based drug-repurposing workflow was used to identify clinically relevant compounds with predicted affinity for a full-length VAV2 structural model. Virtual screening, molecular docking, ADMET prediction, three independent 200-ns molecular-dynamics simulations, principal-component analysis, and MM-PBSA calculations prioritized talazoparib, tivozanib, and isradipine for further evaluation. In THP-1-derived macrophages, talazoparib reduced oxLDL-induced intracellular neutral-lipid accumulation at a sub-cytotoxic concentration. In a complementary DiI-oxLDL assay, all three compounds reduced cell-associated DiI-oxLDL fluorescence relative to vehicle control. These findings provide preliminary computational and cellular support for further investigation of the selected compounds. However, direct binding to or inhibition of VAV2 has not been demonstrated and requires biochemical, genetic, pharmacological, and in vivo validation.