Accelerating optical reporting for conformation of tyrosine kinase inhibitors in solutions

Abstract

The present study has been developing a robust quantum mechanical (QM) conformational sampling method (PrefQMCon) for optical reporting of 4-anilinoquinazoline derivatives based epidermal growth factor receptor (EGFR) tyrosine kinases inhibitors. We use AG-1478 to demonstrate how PrefQMCon helps QM determination of 22 target drug conformer clusters and their properties and UV–vis spectra. In this method, the preferred conformers of AG-1478 are obtained by density functional theory (DFT) optimization from conformational local minimum sampling around the identified rotatable bonds, followed by clustering analysis and time-dependent (TD) DFT calculations for the UV–vis spectra in solvents. Such obtained preferred conformers agree well with earlier experimental measurements where the conformer dependent UV–Vis spectral shift of AG-1478 is as large as ~15 nm. We are further developing this PrefQMCon to study and design other 4-anilinoquinazoline derivatives of EGFR TKIs. Show more