DFT and docking analysis of stability, conformational dynamics, and interaction behavior in linear C6 triketo and diketo scaffolds

Abstract

Abstract Linear polycarbonyl motifs constitute flexible chemical frameworks with relevance to conformational analysis, molecular stability, and interaction modeling. Here, we report a combined density functional theory (DFT) and molecular docking study of the structural stability, conformational preferences, and interaction behavior of linear C₆ triketo and diketo scaffolds. Equilibrium geometries, intramolecular hydrogen-bonding patterns, and relative Gibbs free energies were evaluated at the B3LYP/6–311 +  + G(d,p) level. Symmetric diketone isomers were identified as the most stable conformers, whereas arrangements containing adjacent carbonyl groups exhibited pronounced conformational flexibility accompanied by energetic destabilization of up to ~ 18 kcal mol⁻ 1 . Across the scaffold series, a consistent instability window of ~ 12–16 kcal mol⁻ 1 was observed, associated with characteristic geometric distortions. To qualitatively probe interaction behavior, representative conformers spanning the stability range were subjected to molecular docking. Docking simulations were carried out against three key non-small cell lung cancer (NSCLC)-related targets, epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), to evaluate the biological relevance of the studied conformers and to relate conformational stability to binding behavior in a disease-relevant context. Energetically favorable conformers displayed well-defined and reproducible interaction poses, while less stable structures showed increased orientational variability consistent with their flexible potential energy surfaces.