Structure-Based Virtual Screening Reveals Ibrutinib and Zanubrutinib as Potential Repurposed Drugs against COVID-19.
Int J Mol Sci
; 22(13)2021 Jun 30.
Article
in English
| MEDLINE | ID: covidwho-1288906
ABSTRACT
Coronavirus disease (COVID)-19 is the leading global health threat to date caused by a severe acute respiratory syndrome coronavirus (SARS-CoV-2). Recent clinical trials reported that the use of Bruton's tyrosine kinase (BTK) inhibitors to treat COVID-19 patients could reduce dyspnea and hypoxia, thromboinflammation, hypercoagulability and improve oxygenation. However, the mechanism of action remains unclear. Thus, this study employs structure-based virtual screening (SBVS) to repurpose BTK inhibitors acalabrutinib, dasatinib, evobrutinib, fostamatinib, ibrutinib, inositol 1,3,4,5-tetrakisphosphate, spebrutinib, XL418 and zanubrutinib against SARS-CoV-2. Molecular docking is conducted with BTK inhibitors against structural and nonstructural proteins of SARS-CoV-2 and host targets (ACE2, TMPRSS2 and BTK). Molecular mechanics-generalized Born surface area (MM/GBSA) calculations and molecular dynamics (MD) simulations are then carried out on the selected complexes with high binding energy. Ibrutinib and zanubrutinib are found to be the most potent of the drugs screened based on the results of computational studies. Results further show that ibrutinib and zanubrutinib could exploit different mechanisms at the viral entry and replication stage and could be repurposed as potential inhibitors of SARS-CoV-2 pathogenesis.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Piperidines
/
Pyrazoles
/
Pyrimidines
/
Adenine
/
Protein Kinase Inhibitors
/
Molecular Dynamics Simulation
/
Drug Repositioning
Type of study:
Prognostic study
Limits:
Humans
Language:
English
Year:
2021
Document Type:
Article
Affiliation country:
Ijms22137071
Similar
MEDLINE
...
LILACS
LIS