An integrative omics-guided druggability analysis of VCX2 in hepatocellular carcinoma using Peruvian natural products

Luis Daniel Goyzueta-Mamani; Haruna Luz Barazorda-Ccahuana; Mayron Antonio Candia-Puma; Nadia M Hamdy; Miguel Angel Chávez-Fumagalli

doi:10.3389/fbinf.2026.1822441

An integrative omics-guided druggability analysis of VCX2 in hepatocellular carcinoma using Peruvian natural products

Front Bioinform. 2026 May 18:6:1822441. doi: 10.3389/fbinf.2026.1822441. eCollection 2026.

Authors

Luis Daniel Goyzueta-Mamani¹, Haruna Luz Barazorda-Ccahuana¹, Mayron Antonio Candia-Puma^{1

2}, Nadia M Hamdy³, Miguel Angel Chávez-Fumagalli¹

Affiliations

¹ Computational Biology and Chemistry Research Group, Vicerrectorado de Investigación, Universidad Católica de Santa María, Arequipa, Peru.
² Facultad de Ciencias Farmacéuticas, Bioquímicas y Biotecnológicas, Universidad Católica de Santa María, Arequipa, Peru.
³ Biochemistry and Molecular Biology Department Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.

Abstract

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; ΔG_bind: -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.

Keywords: VCX2; hepatocellular carcinoma (HCC); luteolin-5-O-glucoside; molecular docking; multi-omics integration; natural products; single-cell RNA sequencing; single-cell transcriptomics.