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

Kavli Affiliate: Feng Wang

| First 5 Authors: Sallam Alagawani, Vladislav Vasilyev, Feng Wang, ,

| Summary:

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.

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