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

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.

Radiosynthesis of [11C]Ibrutinib via Pd-Mediated [11C]CO Carbonylation: Preliminary PET Imaging in Experimental Autoimmune Encephalomyelitis Mice

“…All other chemicals were acquired from Sigma-Aldrich (USA or Canada). No-carrier-added [ 11 C]CO 2 was produced on a MC-17 Cyclotron (Scanditronix, Vislanda, Sweden) using the 14 N(p,α) 11 C nuclear reaction in a pressurized gas target containing a nitrogen:oxygen mixture (99.5:0.5) The radiosynthesis was performed using a TracerMaker TM carbon-11 synthesis platform (Scansys Laboratorieteknik, Vaerløse, Denmark). Analytical HPLC was performed on a 1260 infinity II HPLC system (Agilent, Santa Clara, CA, USA) with a M177 γ-radiation detector (Ludlum Instruments, Sweetwater, TX, USA) connected in series after the UV detector.…”

“…Ibrutinib is a first-generation BTK inhibitor used as a chemotherapeutic agent to treat B-cell cancers (10). Although ibrutinib has not been studied clinically as a BTK inhibitor in MS, it has shown efficacy in other autoimmune diseases, such as arthritis, lupus, and recently in treatment of COVID-19 (SARS-CoV-2) (11)(12)(13)(14). The versatility of BTK inhibitors, such as ibrutinib, in treating various B-cell-related diseases has led to their development as radiotracers for positron emission tomography (PET) (15,16).…”

“…Ibrutinib (2) has been labeled at the acrylamide functionality with carbon-11 ( 11 C) using [ 11 C]CO 2 (Figure 1) (16). However, the method resulted in low radiochemical yields (RCYs) (<5%, non-decay corrected) due to side reactions caused by the Grignard reagents, which also affected the chemical purity and radiochemical purity (RCP).…”

“…Radiolabeling of carbonyls such as acrylamides has been extensively reported using [ 11 C]CO 2 (17,18). Recent developments in converting cyclotron-produced [ 11…”

“…11 C]ibrutinib in EAE mouse models of MS using female C57BL/6 mice (EAE score = 2.5) as compared with sham-treated animals (EAE score = 0.0). The sacral region of the spinal is too small in this mouse model to be quickly and reliably extracted.…”