Natural alkaloids as potential EGFR allosteric inhibitors: DFT, molecular docking, and molecular dynamics approach
摘要
Natural alkaloids were computationally investigated as putative allosteric modulators of the epidermal growth factor receptor (EGFR) to explore alternative strategies for overcoming resistance associated with T790M and C797S mutations. Density functional theory (DFT), molecular docking, molecular dynamics (MD), and QTAIM/NCI analyses were combined to evaluate electronic properties, binding affinities, short-time dynamic behavior, and non-covalent interactions. Docking revealed a clear affinity hierarchy, with tabernamine (TBR) showing the strongest interaction (− 9.79 kcal mol−1; Ki = 66 nM), followed by conofoline (CFN) (− 7.57 kcal mol−1; 2.8 µM) and ibogamine (IBN) (− 7.04 kcal mol−1; 6.9 µM). Frontier molecular orbital gaps (7.6–10.1 eV) and density-of-states analyses indicated balanced electronic stability and reactivity, with CFN and LIH displaying enhanced charge-transfer propensity. MD simulations at 310 K demonstrated stable equilibration, where CFN occupied the deepest potential energy well, TBR showed higher mobility, and IBN remained more confined within the allosteric pocket. QTAIM/NCI analyses confirmed stabilizing hydrogen-bonding and dispersion interactions. Predicted ADMET properties suggested high intestinal absorption for all prioritized alkaloids, with CFN exhibiting a comparatively more favorable predicted toxicity profile. Overall, these findings identify natural alkaloids as promising computational hits for EGFR allosteric modulation and provide a basis for further experimental validation within a fourth-generation–inspired, mutant-selective context.