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

Satyavani Kaliamurthi,Chandrabose Selvaraj,Dong-Qing Wei,Gurudeeban Selvaraj,Sanjeev Kumar Singh,Gilles H Peslherbe

doi:10.3390/ijms22137071

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.

Highlights

Many ongoing clinical studies report that ibrutinib and zanubrutinib are able to reduce Coronavirus disease (COVID)-19 disease severity, symptoms and the level of inflammatory cytokines [5,7,33], which is consistent with the molecular docking results of this study
Another study reported that blocking the Bruton’s tyrosine kinase (BTK), TLR3-induced protein kinase B (Akt), mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB signaling pathways enhanced the antiviral responses in mice models [38]
The simulation results, atomic Cα position root-mean-square-deviations (RMSD) and number of hydrogen-bond (HB) interactions, for all drug-target complexes were analyzed with the Visual Molecular Dynamics (VMD) [62] molecular visualization program. Both ibrutinib and zanubrutinib could be repurposed as potential drugs for the treatment of people affected by COVID-19

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Coronavirus disease (COVID)-19 is the leading global health threat to date caused by a coronavirus (SARS-CoV-2 or nCov-2019) next to severe acute respiratory syndrome (SARS). The Middle East respiratory syndrome (MERS) [1,2] in this century. Though antiviral and antimalarial drugs are being used to control and enhance the recovery rate from. COVID-19, the death toll rate is still increasing. There are few vaccine candidates prescribed by the World Health Organization, including BNT162b2, mRNA-1273, Covishield, Sputnik

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Conclusion