Density functional methods study on the structures and spectral characteristics for pharmacophoric conformers, metabolites, and combined fragments of Erlotinib

Erlotinib is an essential drug for the clinical treatment of non-small cell lung cancer, pancreatic cancer, and other cancers. Erlotinib tends to be conformation A rather than the pharmacophoric conformation B in various pharmaceutical cocrystals. The aim of this work is to explore the transformation A to B and spectral characteristics of its metabolites and combined fragments. The conformational transformation mechanism, structures, Raman and UV–Vis spectra of Erlotinib in aqueous solution were systematically calculated by density functional theory B3LYP, CAM-B3LYP, BHandHLYP, LC-ωPBE, and M06-2X methods with 6-311++G( d , p ) basis set. The energy barrier height of conformational transformation is less than 18.0 kJ⋅mol −1 . The Raman and UV–Vis spectra of the drug, its hydrochloride salt, and monohydrate complex in both typical conformations were analyzed comparatively. The calculated results show little difference in electronic energies and relative Gibbs free energies between A and B . All the theoretical results indicate that the characteristic Raman peak of C≡C bond has a blue-shift of more than 80 cm −1 compared with experimental values. Simultaneously, the B3LYP functional is superior to the other four functionals in performance. And the ultraviolet absorption peaks of Erlotinib hydrochloride predicted by B3LYP functional nearly reproduce the experimental results. According to the energetics and spectroscopic characteristics, distinguishing either the Erlotinib itself or its complexes and related metabolites in conformation A or B in aqueous solution requires careful and rigorous analysis. However, the molecular electrostatic potential surface difference of Erlotinib in conformations A and B is noticeable. The epidermal growth factor receptor can accurately recognize conformation B in the human body. The crystal conformation A transforms into the pharmacophoric conformation B easily. The Raman and UV–Vis spectra of the metabolites and combined fragments are significantly different.