Structure-Based Virtual Screening Reveals Ibrutinib and Zanubrutinib as Potential Repurposed Drugs against COVID-19

Area of Science:

• Virology
• Computational Chemistry
• Drug Discovery

Background:

• Coronavirus disease (COVID)-19, caused by SARS-CoV-2, remains a global health threat.
• Bruton's tyrosine kinase (BTK) inhibitors show promise in treating COVID-19 by improving oxygenation and reducing inflammation.
• The precise mechanism of BTK inhibitors in COVID-19 treatment is not fully understood.

Purpose of the Study:

• To computationally screen existing BTK inhibitors for repurposing against SARS-CoV-2.
• To investigate the potential of these inhibitors in targeting viral proteins and host factors involved in COVID-19 pathogenesis.

Main Methods:

• Structure-based virtual screening (SBVS) of nine BTK inhibitors against SARS-CoV-2.
• Molecular docking against viral proteins and host targets (ACE2, TMPRSS2, BTK).
• Molecular mechanics-generalized Born surface area (MM/GBSA) and molecular dynamics (MD) simulations for selected complexes.

Main Results:

• Ibrutinib and zanubrutinib demonstrated the highest potency in computational analyses.
• These drugs show potential to inhibit SARS-CoV-2 at both viral entry and replication stages.
• The study identified potential mechanisms for ibrutinib and zanubrutinib in combating COVID-19.

Conclusions:

• Ibrutinib and zanubrutinib are promising candidates for repurposing as COVID-19 therapeutics.
• Computational screening provides a foundation for further experimental validation.
• Targeting BTK pathways offers a potential strategy against SARS-CoV-2 infection.