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DFT Structural and UV-Vis Spectral Insights into Photosensitivity of Vandetanib: A Dual EGFR/SARS-CoV-2 Mpro
Feng Wang1, Vladislav Vasilyev2
1School of Science, Computing and Emerging Technologies, Swinburne University of Technology, Melbourne, VIC 3122, Australia.
Abstract:
Background: Vandetanib is a clinically approved epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) used in the treatment of medullary thyroid cancer. Recent studies have also suggested potential activity against the SARS-CoV-2 main protease (Mpro), indicating dual therapeutic relevance. However, its clinical use is limited by photosensitivity side effects, the molecular basis of which remains poorly understood. This study aims to elucidate the conformational, spectroscopic, and electronic properties of vandetanib underlying its photoreactivity. Methods: Density functional theory (DFT) was employed to explore vandetanib's conformational landscape, electronic structure, and spectroscopic behavior. Low-energy conformers were identified and compared with experimental crystal and NMR data. Time-dependent DFT (TD-DFT) calculations were used to simulate UV-Vis absorption spectra and assign key electronic transitions. Results: Eight low-energy conformer clusters, including the global minimum structure, were identified. The global minimum was validated by consistency with crystal and experimental NMR data, emphasizing the role of conformational averaging. TD-DFT simulations successfully reproduced the two main UV-Vis absorption bands, with the primary band (~339 nm) assigned to a HOMO-1 → LUMO charge-transfer excitation between the N-methyl piperidine and quinazoline rings, pinpointing a structural contributor to photoreactivity. Additionally, the N-methyl piperidine ring was identified as a major metabolic hotspot, undergoing multiple biotransformations potentially linked to phototoxicity. Conclusions: This study provides molecular-level insights into the structural and photophysical origins of vandetanib's photosensitivity. The findings improve understanding of its adverse effects and can inform the safer design of EGFR-targeting drugs with reduced phototoxic risks.
Insights
Vandetanib
Area of Science:
- Computational Chemistry
- Photochemistry
- Drug Metabolism
Background:
- Vandetanib, an EGFR TKI for medullary thyroid cancer, shows potential against SARS-CoV-2 Mpro.
- Photosensitivity limits vandetanib's clinical use; its molecular basis is unclear.
Purpose of the Study:
- To investigate the conformational, spectroscopic, and electronic properties of vandetanib related to its photoreactivity.
- To understand the molecular mechanisms behind vandetanib-induced photosensitivity.
Main Methods:
- Density Functional Theory (DFT) for conformational analysis and electronic structure.
- Time-Dependent DFT (TD-DFT) for simulating UV-Vis absorption spectra.
- Comparison with experimental crystal and NMR data for validation.
Main Results:
- Eight low-energy conformers of vandetanib were identified, with the global minimum consistent with experimental data.
- TD-DFT accurately simulated UV-Vis spectra, assigning the ~339 nm band to a charge-transfer excitation.
- The N-methyl piperidine ring was identified as a key site for photoreactivity and metabolic transformation.
Conclusions:
- This study reveals the molecular origins of vandetanib's photosensitivity through its photophysical and electronic properties.
- Findings enhance understanding of vandetanib's adverse effects and guide the design of safer EGFR inhibitors.
