Frontiers in bioinformatics · 2026
An integrative omics-guided druggability analysis of VCX2 in hepatocellular carcinoma using Peruvian natural products.
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Goyzueta-Mamani Luis Daniel, Barazorda-Ccahuana Haruna Luz, Candia-Puma Mayron Antonio, Hamdy Nadia M, Chávez-Fumagalli Miguel Angel
Аннотация
INTRODUCTION: Hepatocellular carcinoma (HCC) is among the deadliest cancers, and current biomarkers offer limited diagnostic and therapeutic utility. Identifying novel druggable targets remains a critical challenge for improving HCC management.
METHODS: We implemented an omics-guided computational pipeline integrating single-cell RNA sequencing (scRNA-seq), differential gene expression (DGE) analysis, UMAP clustering, and protein-protein interaction (PPI) network mapping to prioritize candidate genes. Structural characterization of the selected target was performed using AlphaFold-derived models followed by long-timescale molecular dynamics (MD) simulations. Virtual screening of the PeruNPDB (Peruvian Natural Products Database) was conducted using Glide docking, with further evaluation by MM-GBSA and MD-based interaction analyses.
RESULTS: Among prioritized genes (TMBIM4, RGS5, CEACAM7, and VCX2), the cancer/testis antigen VCX2 emerged as a promising candidate due to its aberrant expression and potential involvement in chromosomal instability. MD refinement yielded a stable and ligand-accessible VCX2 conformation. Virtual screening identified luteolin-5-O-glucoside from Equisetum arvense as the top ligand (Glide score: -3.949 ± 0.85 kcal/mol; ΔGbind: -35.43 ± 1.12 kcal/mol). Despite a modest docking score, consistent with the shallow and polar binding site, MM-GBSA and MD simulations supported a thermodynamically favorable and dynamically stable interaction. Key hydrogen bonds with residues Glu68, Thr63, and Ala61 were maintained within a stabilized polar groove.
DISCUSSION: These findings support VCX2 as a potential molecular target in HCC and highlight luteolin-5-O-glucoside as a promising lead scaffold. This study provides a hypothesis-generating framework that integrates single-cell transcriptomics with structure-based druggability analysis, offering new avenues for targeted therapeutic development in HCC.
METHODS: We implemented an omics-guided computational pipeline integrating single-cell RNA sequencing (scRNA-seq), differential gene expression (DGE) analysis, UMAP clustering, and protein-protein interaction (PPI) network mapping to prioritize candidate genes. Structural characterization of the selected target was performed using AlphaFold-derived models followed by long-timescale molecular dynamics (MD) simulations. Virtual screening of the PeruNPDB (Peruvian Natural Products Database) was conducted using Glide docking, with further evaluation by MM-GBSA and MD-based interaction analyses.
RESULTS: Among prioritized genes (TMBIM4, RGS5, CEACAM7, and VCX2), the cancer/testis antigen VCX2 emerged as a promising candidate due to its aberrant expression and potential involvement in chromosomal instability. MD refinement yielded a stable and ligand-accessible VCX2 conformation. Virtual screening identified luteolin-5-O-glucoside from Equisetum arvense as the top ligand (Glide score: -3.949 ± 0.85 kcal/mol; ΔGbind: -35.43 ± 1.12 kcal/mol). Despite a modest docking score, consistent with the shallow and polar binding site, MM-GBSA and MD simulations supported a thermodynamically favorable and dynamically stable interaction. Key hydrogen bonds with residues Glu68, Thr63, and Ala61 were maintained within a stabilized polar groove.
DISCUSSION: These findings support VCX2 as a potential molecular target in HCC and highlight luteolin-5-O-glucoside as a promising lead scaffold. This study provides a hypothesis-generating framework that integrates single-cell transcriptomics with structure-based druggability analysis, offering new avenues for targeted therapeutic development in HCC.