Structural and Spectroscopic Study of the Tyrosine Kinase Inhibitor PD-153035

Abstract

Our study revolves around investigating the spectroscopic properties of the tyrosine kinase inhibitor, PD-153035, both experimentally and theoretically. The UV-Vis absorption spectrum of PD-153035 exhibited four absorption peaks at ca. 220, 250, 330, and 340 nm. The position and relative optical density of the two lowest energy bands at 330 and 340 nm were significantly altered depending on solvent used in UV-Vis measurements. We therefore prompted to computationally examine PD-153035 structures. The potential energy surface scan revealed four energetically stable conformers of PD-153035 calculated through rotation of the dihedral angle between the anilino and quinazolinyl moieties. Two structures have planar conformations while the other two have twisted conformations. The energy difference between the global minimum structure and the highest energy conformer was estimated at 2.12 kcal/mol. The HOMO-LUMO energy gap was calculated at (4.3140 ± 0.0196) eV for the four conformers. The time-dependant Density Functional Theory (td-DFT) calculations employing B3LYP/6-311++G∗∗ level of theory revealed that the 330 nm peak can be attributed to the planar conformers while the 340 nm peak can be due to the twisted conformers. The computed oscillator strength of the planar isomers in various solvents had values double that of the twisted isomers. Taken together, these results showed how the absorption spectrum is sensitive to PD-153035 conformation. Hence, our findings assume relevance in understanding the structure and environment of PD-153035 in the ATP binding pocket of its target proteins. Our future work is to identify the fluorescence spectra of PD-153035 in different solvents and when it bounds to its target proteins. Acknowledgment: Authors acknowledge with gratitude the financial support from Excellerate Australia and iMOVE.