Multi-omics and structure-based drug discovery approach identifies GTPBP4 as a novel CRC target

• Colorectal cancer (CRC) remains a major global health concern with increasing incidence. • A total of 571 DEGs were identified, with 234 significantly downregulated. • Network analysis revealed GTPBP4 as a key hub gene involved in ribosome biogenesis. • A high-quality 3D model of GTPBP4 was generated and validated through multiple structural assessment tools. • Virtual screening of over 2,800 compounds led to the identification of Benzoquinazolinone 12 and IKK Inhibitor VII with strong binding affinity to GTPBP4. • SwissADME and ProTox 3.0 showed favorable pharmacokinetics and manageable toxicity profiles. • Molecular dynamics simulations confirmed structural stability of protein–ligand complexes. • GTPBP4 and top ligands present promising leads for preclinical CRC drug development. Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, emphasizing the urgent need for novel therapeutic targets and effective drug candidates. This study employed an integrated bioinformatics, transcriptomic, and in silico approach to identify key molecular drivers and natural inhibitors for CRC therapy. Publicly available microarray data (GSE37182) consisting of 172 samples, 88 normal and 84 tumor tissues, were analyzed to identify differentially expressed genes (DEGs). GEO2R was used for the detection, a total of 571 DEGs were detected, among which 234 were significantly downregulated and subjected to Gene Ontology (GO) and KEGG pathway enrichment analysis. These genes were primarily involved in ribosome biogenesis, RNA splicing, and protein folding pathways. Protein-protein interaction (PPI) network analysis highlighted GTPBP4 as a top hub gene. These results suggest that GTPBP4 may represent a candidate molecular target for further experimental investigation. Due to the absence of an experimentally resolved structure, a 3D model of GTPBP4 was generated via Chai-1 lab discovery and validated via Ramachandran plot analysis, ERRAT, and ProSA-web (Z-score: −8.14; quality factor: 86.871), confirming its structural reliability. Active site prediction was conducted by DrugRep. Two libraries were docked with the GTPBP4, the natural compounds and small molecule inhibitors were retrieved from Pubchem database. Molecular docking and Virtual screening were conducted on Easy Dock vina 2.0 using 1,862 natural products and 1,024 small-molecule inhibitors. Benzoquinazolinone 12 and IKK Inhibitor VII exhibited the strongest binding affinities (−9.1 and −9.0 kcal/mol, respectively) toward GTPBP4. ADMET analysis was performed on SwissADME and ProTox 3.0 revealing favorable pharmacokinetic profiles with manageable toxicity risks, while molecular dynamics simulations performed on CABS Flex 2.0 confirmed the stability of the protein–ligand complexes. GTPBP4 was identified as a differentially expressed hub gene that may play regulatory roles in colorectal cancer and warrants further experimental validation.