Optical spectra and conformation pool of tyrosine kinase inhibitor PD153035 using a robust quantum mechanical conformation search

Abstract

Tyrosine kinase inhibitors (TKIs) based on the quinazoline-aniline scaffold represent a significant class of small molecule drugs for diseases such as cancer. The present study applies a recently developed robust quantum mechanical conformer (QMC) search for possible conformers of potent TKI PD15035 systematically, in order to investigate the resultant UV-vis spectral changes at the molecular level in silico. The analysis suggests that the profiles of the optical spectra of PD153035 are sensitive to the conformers and environment, such as solvents. Two major synthesised optical spectral bands at 330 nm and 327 nm in dimethyl sulfoxide (DMSO) solvent agree with UV-vis spectral measurements at 330–340 nm. This study further reveals that the optical spectral band widths (Δλ) of PD153035 expand from 10.24 nm in the gas phase to 13.17 nm in toluene and hits a plateau of ∼15 nm for more polar solvents such as methanol. The study finishes by providing simulated UV-vis spectral information regarding the differences between TKI-Cl (AG-1478) and TKI-Br (PD153035), which can be useful information to study the X-impact on the potency of the TKIs in the future.