Accelerating optical reporting for conformation of tyrosine kinase inhibitors in solutions

Abstract

AbstractThe 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.