Integrative Multi-Omics and Molecular Simulations Identify PRKCD as a Biological Modulator in Colon Adenocarcinoma: Validation With Phoenix dactylifera Phytochemicals and Comparison With Rottlerin.

Colorectal cancer (CRC) is the leading cause of cancer-related deaths worldwide. Colon adenocarcinoma (COAD), the most common histological subtype, is characterized by a poor prognosis in advanced stages due to significant molecular heterogeneity. Protein kinase C delta (PKCδ), encoded by PRKCD, is a context-dependent regulatory kinase in tumor biology. Its expression, genomic alterations, and binding interactions with phytochemicals from Phoenix dactylifera were studied using a comprehensive in silico approach. PRKCD was found to be downregulated in all TCGA-COAD tumor subgroups when compared to normal tissue. The survival analysis failed to show a statistically significant association between PRKCD expression and overall or disease-free survival; thus, the protein is more likely to be a biological modulator than a prognostic marker. Mutational profiling revealed missense substitutions and copy number variations in COAD. The drug-like properties of 46 phytochemicals from P. dactylifera were evaluated, and only five compounds passed all the filters. Docking against the C2 regulatory domain of PKCδ (PDB ID: 1YRK) revealed (Z)-4-Methoxy-3,3',5,5'-tetrahydroxystilbene (PubChem CID: 13499471) as the highest-scoring ligand at -7.0 kcal/mol. Rottlerin, the validated PKCδ inhibitor, was used as a positive control and had a score of -7.3 kcal/mol at the same binding site. Both complexes were subjected to 100 ns molecular dynamics (MD) simulations under equated conditions. Several parameters, including backbone RMSD, RMSF, radius of gyration (Rg), solvent-accessible surface area (SASA), hydrogen-bond counts, principal component analysis (PCA), and free-energy landscape (FEL) profiling, all indicated stable conformations for the two complexes. The lead phytocompound showed very similar behaviour to the positive control, thereby reinforcing its potential as a PRKCD modulator. The results indicate that further experimental studies on P. dactylifera-derived stilbenoids in COAD are warranted.

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