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Updated: Nov 30, 2025
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Published on: May 9, 2025
Modelling the structural and reactivity landscapes of tucatinib with special reference to its wavefunction-dependent
Ali Alsalme1, T Pooventhiran2, Nabil Al-Zaqri1
1Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia.
Abstract:
HER-2 type breast cancer is one of the most aggressive malignancies found in women. Tucatinib is recently developed and approved as a potential medicine to fight this disease. In this manuscript, we present the gross structural features of this compound and its reactivity and wave function properties using computational simulations. Density functional theory was used to optimise the ground state geometry of the molecule and molecular docking was used to predict biological activity. As the electrons interact with electromagnetic radiations, electronic excitations between different energy levels are analysed in detail using time-dependent density functional theory. Various intermolecular and intermolecular interactions are analysed and reaction sites for attacking electrophiles and nucleophiles identified. Information entropy calculations show that the compound is inherently stable. Docking with COVID-19 proteins show docking score of - 9.42, - 8.93, - 8.45 and - 8.32 kcal/mol respectively indicating high interaction between the drug and proteins. Hence, this is an ideal candidate to study repurposing of existing drugs to combat the pandemic.
Insights
Tucatinib, a drug for HER2-positive breast cancer, shows high stability and potential for repurposing against COVID-19 based on computational analysis. Further studies are recommended for drug repurposing to combat the pandemic.
Area of Science:
- Computational chemistry and drug discovery.
Background:
- HER2-type breast cancer is an aggressive malignancy.
- Tucatinib is a newly approved medication for this condition.
Purpose of the Study:
- To investigate the structural, reactivity, and electronic properties of Tucatinib using computational methods.
- To explore the potential of Tucatinib for drug repurposing against COVID-19.
Main Methods:
- Density Functional Theory (DFT) for geometry optimization.
- Time-Dependent DFT (TD-DFT) for electronic excitations.
- Molecular docking simulations for biological activity prediction.
Main Results:
- Tucatinib exhibits inherent stability based on information entropy calculations.
- Computational analysis revealed key intermolecular interactions and reactive sites.
- Molecular docking against COVID-19 proteins yielded significant negative binding scores, indicating strong interactions.
Conclusions:
- Tucatinib possesses favorable computational properties for its known application.
- The drug demonstrates potential for repurposing in combating the COVID-19 pandemic due to strong predicted interactions with viral proteins.
