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Updated: Nov 12, 2025
Covalent Fragment Screening Using the Quantitative Irreversible Tethering Assay
Published on: February 28, 2025
Structural investigations, quantum mechanical studies on proton and metal affinity and biological activity
Nabil Al-Zaqri1,2, T Pooventhiran3, Fahad A Alharthi1
1Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.
Abstract:
Cancer of the lungs and thyroid is particularly difficult to manage and treat. Notably, selpercatinib has recently been suggested as an effective drug to combat these diseases. The entire world is currently tackling the pandemic caused by the SARS-CoV-19 virus. Numerous pharmaceuticals have been evaluated for the management of the disease caused by SARS-CoV-19 (i.e., COVID-19). In this study, selpercatinib was proposed as a potential inhibitor of different SARS-CoV-19 proteins. Several intriguing effects of the molecule were found during the conducted computational investigations. Selpercatinib could effectively act as a proton sponge and exhibited high proton affinity in solution. Moreover, it was able to form complexes with metal ions in aqueous solutions. Specifically, the compound displayed high affinity towards zinc ions, which are important for the prevention of virus multiplication inside human cells. However, due to their charge, zinc ions are not able to pass the lipid bilayer and enter the cell. Thus, it was determined that selpercatinib could act as an ionophore, effectively transporting active zinc ions into cells. Furthermore, various quantum mechanical analyses, including energy studies, evaluation of the reactivity parameters, examination of the electron localisation and delocalisation properties, as well as assessment of the nonlinear optical (NLO) properties and information entropy, were conducted herein. The performed docking studies (docking scores -9.3169, -9.1002, -8.1853 and -8.1222 kcal mol-1) demonstrated that selpercatinib strongly bound with four isolated SARS-CoV-2 proteins.
Insights
Selpercatinib shows potential against SARS-CoV-2 by acting as a proton sponge and ionophore, delivering zinc into cells. Computational studies confirm its strong binding to key SARS-CoV-2 proteins, suggesting a novel therapeutic avenue.
Area of Science:
- Computational chemistry
- Drug discovery
- Virology
Background:
- Lung and thyroid cancers are challenging to treat.
- SARS-CoV-2 (COVID-19) pandemic necessitates new therapeutic strategies.
- Selpercatinib is an emerging drug for certain cancers.
Purpose of the Study:
- To investigate selpercatinib as a potential inhibitor of SARS-CoV-2 proteins.
- To explore the molecular mechanisms of selpercatinib against the virus.
- To evaluate selpercatinib's potential as a drug delivery agent for zinc.
Main Methods:
- Computational investigations including quantum mechanical analyses.
- Proton sponge and metal ion complexation studies.
- Molecular docking studies against isolated SARS-CoV-2 proteins.
Main Results:
- Selpercatinib demonstrated high proton affinity and formed complexes with metal ions, notably zinc.
- The compound functions as an ionophore, facilitating zinc ion transport into cells.
- Docking studies revealed strong binding affinities (up to -9.3169 kcal mol⁻¹) with four SARS-CoV-2 proteins.
Conclusions:
- Selpercatinib exhibits promising antiviral properties against SARS-CoV-2 through multiple mechanisms.
- Its ability to act as a proton sponge and ionophore, coupled with strong protein binding, warrants further investigation.
- Selpercatinib represents a potential candidate for COVID-19 treatment development.
