Benchmarking the performance of DFT functionals for absorption and fluorescence spectra of EGFR inhibitor AG-1478 using TD-DFT

Abstract

Optical spectra (UV-vis and fluorescence) are sensitive to the chemical environment and conformation of fluorophores and therefore, are ideal probes for their conformation and solvent responses. Tyrosine kinase inhibitors (TKI) such as AG-1478 of epidermal growth factor receptor (EGFR) when containing a quinazolinamine scaffold are fluorophores. Conformers of AG-1478 have been confirmed by both experiment and theory. It is, however, very important to benchmark computational methods such as DFT functionals against optical spectral measurements, when time-dependent density functional theory (TD-DFT) is applied to study the fluorophores. 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, B3PW91, B3LYP, B3P86, BPE1BPE, APFD, HSEH1PBE, and N12SX DFT-VXC functionals are the top performers. Beckes three-parameter exchange functional (B3) tends to generate accurate optical spectra over other exchange functionals. The B3PW91 functional is the recommended DFT functional for optical property calculations of this class of TKIs whereas B3LYP is excellent for absorption calculations and B3P86 is best for emission calculations. Any 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 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.