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

Wang, Rui; Vasilyev, V. V.; Clayton, Andrew H. A.

doi:10.1039/d1nj04348j

Cited by 2 publications

(3 citation statements)

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“…This finding agrees with prior studies conducted using DFT-B3LYP. In our study, the absorption peak wavelengths of the global minimum structures for Br and Cl are 329.99 and 329.88, respectively, compared to 331.77 for Br and 331.02 for Cl in the previous study [16,19]. Figure 5 compares the entire UV-Vis absorption spectrum in a DMSO solvent ranging from 180 to 350 nm for the more potent TKIs, (a) TKI-Br and (b) TKI-Cl, which exhibit a different pattern compared to the others, H, F, and I.…”

Section: Changes In the Uv-visible Spectra Of The Tkis-x Conformerscontrasting

confidence: 39%

Section: Resultsmentioning

confidence: 47%

“…Figure 1 depicts the observed pattern in the strain energies (SEs) of the five low-energy conformations within the DMSO solvent for each TKI-X, in comparison to their corresponding individual global minimum structure, along with the structures retrieved from the EGFR database (http://crdd.osdd.net/raghava/egfrindb/, accessed on 2 February 2023). The energies of the final structures (EGFR-DB) were optimized with the torsion angles held constant [16]. Furthermore, Figure 1 illustrates the considerable diversity in SE for the EGFR database structures.…”

Section: Conformation Changes In Tki-xs Due To Halogen Substitution A...mentioning

confidence: 99%

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Insights into Halogen-Induced Changes in 4-Anilinoquinazoline EGFR Inhibitors: A Computational Spectroscopic Study

Alagawani,

Vasilyev,

Clayton

et al. 2024

Molecules

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The epidermal growth factor receptor (EGFR) is a pivotal target in cancer therapy due to its significance within the tyrosine kinase family. EGFR inhibitors like AG-1478 and PD153035, featuring a 4-anilinoquinazoline moiety, have garnered global attention for their potent therapeutic activities. While pre-clinical studies have highlighted the significant impact of halogen substitution at the C3’-anilino position on drug potency, the underlying mechanism remains unclear. This study investigates the influence of halogen substitution (X = H, F, Cl, Br, I) on the structure, properties, and spectroscopy of halogen-substituted 4-anilinoquinazoline tyrosine kinase inhibitors (TKIs) using time-dependent density functional methods (TD-DFT) with the B3LYP functional. Our calculations revealed that halogen substitution did not induce significant changes in the three-dimensional conformation of the TKIs but led to noticeable alterations in electronic properties, such as dipole moment and spatial extent, impacting interactions at the EGFR binding site. The UV–visible spectra show that more potent TKI-X compounds typically have shorter wavelengths, with bromine’s peak wavelength at 326.71 nm and hydrogen, with the lowest IC50 nM, shifting its lambda max to 333.17 nm, indicating a correlation between potency and spectral characteristics. Further analysis of the four lowest-lying conformers of each TKI-X, along with their crystal structures from the EGFR database, confirms that the most potent conformer is often not the global minimum structure but one of the low-lying conformers. The more potent TKI-Cl and TKI-Br exhibit larger deviations (RMSD > 0.65 Å) from their global minimum structures compared to other TKI-X (RMSD < 0.15 Å), indicating that potency is associated with greater flexibility. Dipole moments of TKI-X correlate with drug potency (ln(IC50 nM)), with TKI-Cl and TKI-Br showing significantly higher dipole moments (>8.0 Debye) in both their global minimum and crystal structures. Additionally, optical spectral shifts correlate with potency, as TKI-Cl and TKI-Br exhibit blue shifts from their global minimum structures, in contrast to other TKI-X. This suggests that optical reporting can effectively probe drug potency and conformation changes.

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Section: Changes In the Uv-visible Spectra Of The Tkis-x Conformerscontrasting

confidence: 39%

Section: Resultsmentioning

confidence: 47%

Section: Conformation Changes In Tki-xs Due To Halogen Substitution A...mentioning

confidence: 99%

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Insights into Halogen-Induced Changes in 4-Anilinoquinazoline EGFR Inhibitors: A Computational Spectroscopic Study

Alagawani,

Vasilyev,

Clayton

et al. 2024

Molecules

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Future of computational molecular spectroscopy—from supporting interpretation to leading the innovation

Wang

2023

Phys. Chem. Chem. Phys.

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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 the recently developed robust...

Cited by 2 publications

References 17 publications

Insights into Halogen-Induced Changes in 4-Anilinoquinazoline EGFR Inhibitors: A Computational Spectroscopic Study

Insights into Halogen-Induced Changes in 4-Anilinoquinazoline EGFR Inhibitors: A Computational Spectroscopic Study

Future of computational molecular spectroscopy—from supporting interpretation to leading the innovation

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