Multi-Layer Computational Prioritisation of Platinum-Resistance Inhibitors in Colorectal Cancer: Transcriptomic Stratification, Multi-Target Docking, and Integrated Candidate Ranking

Abstract Background. Oxaliplatin resistance is a principal driver of treatment failure in advanced colorectal cancer (CRC). Its molecular basis involves converging DNA-repair, redox, and iron-metabolism programmes, but no computational study has integrated transcriptomic resistance stratification with multi-target docking across this full set of pathways. Methods. We assembled a 14-gene platinum-resistance panel and stratified 436 TCGA-COAD primary tumours into High-Resistance (n=274) and Low-Resistance (n=162) clusters by unsupervised k-means clustering on z-scored expression data. Differential expression was assessed by Mann–Whitney U with Benjamini–Hochberg correction. Six top-ranked candidates were docked against three validated structures: SLC7A11 (PDB 7EPF, 2.70Å), ERCC1–XPF (PDB 2BGS, 1.64Å), and CTR1 (PDB 7MHK, 1.96Å) using AutoDock Vina. Docking was validated by redocking (RMSD 1.315Å) and active/decoy discrimination (ROC-AUC=0.947, EF@10%=4.0×). Candidates were ranked by a weighted composite score integrating docking affinities and drug-likeness. Results. Thirteen of 14 genes reached FDR<0.05 in the resistance contrast; ERCC1 did not (FDR=0.243), despite being a classical platinum-resistance mediator. SLC7A11 showed the largest upregulation (log₂FC=+1.10, FDR=4.6×10⁻²⁷). TFRC, ACSL4, and SLC7A11 were co-upregulated, consistent with a ferroptosis-primed but protected phenotype. KRAS status was not associated with resistance cluster (Chi² p=0.421). Erastin ranked first (composite 8.60) with strong affinity for all three targets (SLC7A11 −10.5; ERCC1-XPF −6.1; CTR1 −8.3 kcal/mol). NSC16168, the most fragment-like compound (MW=212 Da), ranked third with strong SLC7A11 (−8.9 kcal/mol) and CTR1 (−8.1 kcal/mol) affinities, leaving extensive chemical space for lead optimisation. Conclusions. Oxaliplatin resistance in CRC is transcriptomically dominated by SLC7A11 upregulation rather than ERCC1 overexpression, pointing to ferroptosis suppression as the primary resistance axis. Erastin and NSC16168 emerge as dual-pathway candidates warranting in vitro validation in isogenic oxaliplatin-resistant CRC lines.