Montelukast is a dual-purpose inhibitor of SARS-CoV-2 infection and virus-induced IL-6 expression identified by structure-based drug repurposing
| Autor: | Max Luedemann, Daniela Stadler, Cho-Chin Cheng, Ulrike Protzer, Percy A. Knolle, Sainitin Donakonda |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
RBD
Receptor binding domain Biophysics Biochemistry MM-PBSA molecular mechanics – Poisson Boltzmann surface area Article Rg Radius of gyration Docking Binding site similarity QMEAN Qualitative Model Energy Analysis Neutralization Structural Biology ACE2 Angiotensin-converting enzyme 2 Drug ReposER Drug REPOsitioning Exploration Resource Genetics PME Particle-Mesh Ewald PME Structural modeling RMSD root-mean-square deviation skin and connective tissue diseases ComputingMethodologies_COMPUTERGRAPHICS RMSF root-mean-square fluctuation Molecular dynamics simulations SARS-CoV-2 fungi Structural Modeling Binding Site Similarity Molecular Dynamics Simulations Sars-cov-2 Computer Science Applications respiratory tract diseases body regions SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2 GQME Global Model Quality Estimation TP248.13-248.65 Biotechnology |
| Zdroj: | Computational and Structural Biotechnology Journal, Vol 20, Iss, Pp 799-811 (2022) Computational and Structural Biotechnology Journal Comp. Struc. Biotech. J. 20, 799-811 (2022) |
| ISSN: | 2001-0370 |
| Popis: | Graphical abstract Drug-repurposing has been instrumental to identify drugs preventing SARS-CoV-2 replication or attenuating the disease course of COVID-19. Here, we identify through structure-based drug-repurposing a dual-purpose inhibitor of SARS-CoV-2 infection and of IL-6 production by immune cells. We created a computational structure model of the receptor binding domain (RBD) of the SARS-CoV-2 spike 1 protein, and used this model for insilico screening against a library of 6171 molecularly defined binding-sites from drug molecules. Molecular dynamics simulation of candidate molecules with high RBD binding-scores in docking analysis predicted montelukast, an antagonist of the cysteinyl-leukotriene-receptor, to disturb the RBD structure, and infection experiments demonstrated inhibition of SARS-CoV-2 infection, although montelukast binding was outside the ACE2-binding site. Molecular dynamics simulation of SARS-CoV-2 variant RBDs correctly predicted interference of montelukast with infection by the beta but not the more infectious alpha variant. With distinct binding sites for RBD and the leukotriene receptor, montelukast also prevented SARS-CoV-2-induced IL-6 release from immune cells. The inhibition of SARS-CoV-2 infection through a molecule binding distal to the ACE-binding site of the RBD points towards an allosteric mechanism that is not conserved in the more infectious alpha and delta SARS-CoV-2 variants. |
| Databáze: | OpenAIRE |
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