Dual-Target Network Pharmacology of NUDT1 and CDK4 in Therapy-Resistant Non-Small-Cell Lung Cancer
Keywords:
NUDT1, CDK4, non-small-cell lung cancer, network pharmacology, resistance, systems biologyAbstract
Background: Therapy-resistant non-small-cell lung cancer (NSCLC) frequently displays simultaneous oxidative-stress adaptation and deregulated cell-cycle signalling.
Objective: We investigated whether NUDT1 and CDK4 occupy a shared resistance network that could be addressed by multi-target small molecules.
Methods: Disease-associated genes were assembled from four curated databases and intersected with predicted targets of 186 drug-like heterocyclic compounds. Protein–protein interaction analysis, centrality scoring and pathway enrichment were used to define a resistance module. Candidate compounds were docked to NUDT1 and CDK4, followed by 80-ns simulations of the leading dual-target complexes.
Results: The integrated network contained 143 resistance-linked genes, of which 18 formed a high-centrality module enriched for G1/S transition, oxidative DNA-damage response, PI3K-AKT signalling and apoptosis regulation. NUDT1 and CDK4 were connected through six shared first-neighbour proteins, including MYC, RB1 and TP53-associated nodes. Compound HET-38 ranked within the top five for both targets and demonstrated docking scores of -10.1 kcal/mol for NUDT1 and -9.3 kcal/mol for CDK4. During simulation, HET-38 maintained stable contact networks without progressive backbone drift; calculated binding free energies were -39.5±6.1 and -35.7±5.4 kcal/mol, respectively. In silico pharmacokinetic assessment suggested high intestinal absorption, no major pan-assay interference alerts and a moderate CYP3A4 interaction risk.
Conclusion: A convergent NUDT1–CDK4 network is computationally plausible in resistant NSCLC and can be interrogated using dual-target discovery strategies. HET-38 emerged as a lead for orthogonal enzyme assays and resistance-model testing, while the network analysis provides a mechanistic framework for future combination or polypharmacology studies.
Publication format: research abstract. No full-text manuscript accompanies this record.
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