{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T01:37:46Z","timestamp":1782869866691,"version":"3.54.5"},"reference-count":48,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T00:00:00Z","timestamp":1756425600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>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\u2019s 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\u2013Vis 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\u2013Vis absorption bands, with the primary band (~339 nm) assigned to a HOMO\u20131 \u2192 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\u2019s photosensitivity. The findings improve understanding of its adverse effects and can inform the safer design of EGFR-targeting drugs with reduced phototoxic risks.<\/jats:p>","DOI":"10.3390\/ph18091297","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T16:18:15Z","timestamp":1756484295000},"page":"1297","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["DFT Structural and UV\u2013Vis Spectral Insights into Photosensitivity of Vandetanib: A Dual EGFR\/SARS-CoV-2 Mpro Inhibitor"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6584-0516","authenticated-orcid":false,"given":"Feng","family":"Wang","sequence":"first","affiliation":[{"name":"School of Science, Computing and Emerging Technologies, Swinburne University of Technology, Melbourne, VIC 3122, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0817-5641","authenticated-orcid":false,"given":"Vladislav","family":"Vasilyev","sequence":"additional","affiliation":[{"name":"National Computational Infrastructure, Australian National University, Canberra, ACT 0200, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Alagawani, I., and Wang, F. 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