Optical spectra of EGFR inhibitor AG-1478 for benchmarking DFT functionals

Optical spectroscopy (UV-vis and fluorescence spectroscopy) is sensitive to the chemical environment and conformation of fluorophores and therefore, serves as an ideal probe for the conformation and solvent responses. Tyrosine kinase inhibitors (TKI) such as AG-1478 of epidermal growth factor receptor when containing a quinazolinamine scaffold are fluorophores. It is, however, very important to benchmark density functional theory (DFT) method against optical spectral measurements, when time-dependent DFT is applied. In this study, the performance of up to 22 DFT functionals is benchmarked with respect to the measured optical spectra of AG-1478 in dimethyl sulfoxide (DMSO) solvent. It is discovered when combined with the 6-311++G(d, p) basis set, there are top seven functionals; B3PW91, B3LYP, B3P86, PBE1PBE, APFD, HSEH1PBE, and N12SX DFT-V-XC functionals are identified as the top performers. Becke's three-parameter exchange functional (B3) tends to generate accurate optical spectra to form the best three functionals, B3LYP, B3PW91 and B3P86. Specifically, B3PW91 was recommended for studying the optical properties of 4-quinazolinamine TKIs, B3LYP was found to be excellent for absorption spectrum, while B3P86 was identified as the best for emission spectrum. Any further corrections to B3LYP, such as CAM-B3LYP, LC-B3LYP, and B3LYP-D3 result in larger errors in the optical spectra of AG-1478 in DMSO solvent. These best three (B3Vc) functionals are reliable tools for optical properties of the TKIs and therefore the design of new agents with larger Stokes shift for medical image applications. To obtain reliable optical spectra for this class of 4-quinazolinamine based TKIs, it is important to include the electron correlation energy.