Current drug targets · 2026
Drug Repurposing in Lung Cancer (NSCLC): Dual CDK1/TOP2A Targeting by Sertraline and Enoxacin.
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Kar Musa
Аннотация
INTRODUCTION: Non-small cell lung cancer (NSCLC), encompassing lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), remains a global health challenge due to subtype-specific resistance. Targeting shared molecular machinery between these subtypes offers a strategic advantage to overcome histological differences and bypass signalling.
METHODS: We employed an integrated in silico pipeline: transcriptomic analysis of GSE159857 validated against large-scale TCGA-LUAD and TCGA-LUSC cohorts, protein-protein interaction (PPI) network construction (STRING confidence ≥ 0.7), and ADMET filtering. Structure-based molecular docking was performed on CDK1 (PDB 5LQF) and TOP2A in both apo- (PDB 9BQB) and DNA-bound (PDB 4FM9) states to validate target engagement.
RESULTS: A core set of 1105 commonly upregulated genes was identified. Topological analysis prioritised CDK1 (Degree 232) and TOP2A (Degree 219) as central hub proteins. Sertraline and Enoxacin exhibited potent binding affinities (-9.7 to -8.3 kcal/mol). Validation using the DNAbound TOP2A complex confirmed stable ternary interactions at the catalytic interface with affinities of -6.3 to -6.5 kcal/mol and a redocking RMSD < 2.0 Å.
DISCUSSION: The predicted engagement is driven by polypharmacology and structural mimicry rather than functional serotonin signalling. This dual-inhibitory mechanism likely reconciles previously reported anti-neoplastic phenotypes like ROS formation and autophagy by acting as an upstream enzymatic blockade.
CONCLUSION: This study identifies sertraline and enoxacin as high-priority, dual-target candidates, providing a robust structural rationale for their rapid clinical repositioning in NSCLC therapy.
METHODS: We employed an integrated in silico pipeline: transcriptomic analysis of GSE159857 validated against large-scale TCGA-LUAD and TCGA-LUSC cohorts, protein-protein interaction (PPI) network construction (STRING confidence ≥ 0.7), and ADMET filtering. Structure-based molecular docking was performed on CDK1 (PDB 5LQF) and TOP2A in both apo- (PDB 9BQB) and DNA-bound (PDB 4FM9) states to validate target engagement.
RESULTS: A core set of 1105 commonly upregulated genes was identified. Topological analysis prioritised CDK1 (Degree 232) and TOP2A (Degree 219) as central hub proteins. Sertraline and Enoxacin exhibited potent binding affinities (-9.7 to -8.3 kcal/mol). Validation using the DNAbound TOP2A complex confirmed stable ternary interactions at the catalytic interface with affinities of -6.3 to -6.5 kcal/mol and a redocking RMSD < 2.0 Å.
DISCUSSION: The predicted engagement is driven by polypharmacology and structural mimicry rather than functional serotonin signalling. This dual-inhibitory mechanism likely reconciles previously reported anti-neoplastic phenotypes like ROS formation and autophagy by acting as an upstream enzymatic blockade.
CONCLUSION: This study identifies sertraline and enoxacin as high-priority, dual-target candidates, providing a robust structural rationale for their rapid clinical repositioning in NSCLC therapy.