Integrative Multi-Omics and Structure-based Analysis of DHODH Reveals its Therapeutic Potential in Colorectal Cancer
Md. Ramjan Sheikh, Md. Shahidul Islam, Md Misbah Uddin Shakib, Chowdhury Lutfun Nahar Metu, Md. Sajidur Rahman, Jarin Tasnim, Rajeshwari Das Raima, Md. Hasan, Susmita Paul, Mst Ismot Jahan, Md. Ekhlas UddinDihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme involved in de novo pyrimidine biosynthesis and has emerged as a potential target in cancer metabolism and therapy. This study integrated transcriptomic analysis with structure-based drug discovery to investigate the biological significance and therapeutic potential of DHODH in colorectal cancer (COAD and READ). TCGA-COAD and TCGA-READ RNA-seq data were analyzed for differential expression, clinical association, survival, pathway enrichment, immune infiltration, and therapeutic relevance, with GSE44076 used for external validation. DHODH was significantly elevated in colorectal cancer, while its expression showed limited association with overall survival. Enrichment and immune analyses suggested that DHODH may be associated with immune-related processes and the tumor immune microenvironment. CCLE/DepMap analysis further indicated DHODH dependency in a subset of colorectal cancer cell lines. Structure-based virtual screening identified several promising compounds, including (+)-Luguine, Benzyl 2-[(2-cinnamylidene-3-oxo-1-benzofuran-6-yl)oxy]acetate, 2,3,5-trimethyl-6-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)-7H-furo[3,2-g]chromen-7-one, and N-[2-(4-methylphenyl)ethyl]-2-(2-oxo-1,2-dihydroquinolin-3-yl)acetamide. Molecular docking and 100 ns molecular dynamics simulations supported stable ligand-DHODH interactions. MM/PBSA analysis showed favorable binding free energies ranging from -4.98 to -7.69 kcal/mol, with the DHODH-(+)-Luguine complex exhibiting the most favorable predicted binding energy. ADMET analysis further indicated generally acceptable drug-like and pharmacokinetic properties, although compound-specific toxicity concerns were identified. Overall, DHODH may represent a promising therapeutic target in colorectal cancer, while the identified compounds provide potential candidates for further experimental validation as DHODH inhibitors.