表皮生长因子受体(EGFR)由于其在酪氨酸激酶家族中的重要性而成为癌症治疗中的关键靶标。EGFR抑制剂,如AG-1478和PD153035,具有4-苯胺基喹唑啉部分,因其有效的治疗活动而受到全球关注。虽然临床前研究强调了C3'-苯胺基位的卤素取代对药物效力的显著影响,潜在机制尚不清楚.本研究调查了卤素取代的影响(X=H,F,Cl,Br,I)在结构上,属性,和使用具有B3LYP功能的时间依赖性密度功能方法(TD-DFT)的卤素取代的4-苯胺喹唑啉酪氨酸激酶抑制剂(TKIs)的光谱学。我们的计算表明,卤素取代不会引起TKI三维构象的显着变化,但会导致电子性质的显着变化,如偶极矩和空间范围,影响EGFR结合位点的相互作用。紫外可见光谱表明,更有效的TKI-X化合物通常具有更短的波长,溴的峰值波长为326.71nm,氢,具有最低的IC50nM,将其λmax移至333.17nm,表明效力和光谱特征之间的相关性。进一步分析每个TKI-X的四个最低位构象,以及它们来自EGFR数据库的晶体结构,证实了最有效的构象通常不是全局最小结构,而是低洼的构象之一。与其他TKI-X(RMSD<0.15bias)相比,更有效的TKI-Cl和TKI-Br与其全球最小结构的偏差更大(RMSD>0.65bias),表明效力与更大的灵活性有关。TKI-X的偶极矩与药物效力(ln(IC50nM))相关,TKI-Cl和TKI-Br在其整体最小值和晶体结构中均显示出显着更高的偶极矩(>8.0德拜)。此外,光谱偏移与效力相关,由于TKI-Cl和TKI-Br从其全球最小结构表现出蓝色变化,与其他TKI-X相比。这表明光学报告可以有效地探测药物效力和构象变化。
The epidermal growth factor receptor (EGFR) is a pivotal target in cancer therapy due to its significance within the tyrosine kinase family. EGFR inhibitors like AG-1478 and PD153035, featuring a 4-anilinoquinazoline moiety, have garnered global attention for their potent therapeutic activities. While pre-clinical studies have highlighted the significant impact of halogen substitution at the C3\'-anilino position on drug potency, the underlying mechanism remains unclear. This
study investigates the influence of halogen substitution (X = H, F, Cl, Br, I) on the structure, properties, and spectroscopy of halogen-substituted 4-anilinoquinazoline tyrosine kinase inhibitors (TKIs) using time-dependent density functional methods (TD-DFT) with the B3LYP functional. Our calculations revealed that halogen substitution did not induce significant changes in the three-dimensional conformation of the TKIs but led to noticeable alterations in electronic properties, such as dipole moment and spatial extent, impacting interactions at the EGFR binding site. The UV-visible spectra show that more potent TKI-X compounds typically have shorter wavelengths, with bromine\'s peak wavelength at 326.71 nm and hydrogen, with the lowest IC50 nM, shifting its lambda max to 333.17 nm, indicating a correlation between potency and spectral characteristics. Further analysis of the four lowest-lying conformers of each TKI-X, along with their crystal structures from the EGFR database, confirms that the most potent conformer is often not the global minimum structure but one of the low-lying conformers. The more potent TKI-Cl and TKI-Br exhibit larger deviations (RMSD > 0.65 Å) from their global minimum structures compared to other TKI-X (RMSD < 0.15 Å), indicating that potency is associated with greater flexibility. Dipole moments of TKI-X correlate with drug potency (ln(IC50 nM)), with TKI-Cl and TKI-Br showing significantly higher dipole moments (>8.0 Debye) in both their global minimum and crystal structures. Additionally, optical spectral shifts correlate with potency, as TKI-Cl and TKI-Br exhibit blue shifts from their global minimum structures, in contrast to other TKI-X. This suggests that optical reporting can effectively probe drug potency and conformation changes.