Anin silicoanalysis of Ibuprofen enantiomers in high concentrations of sodium chloride with SARS-CoV-2 main protease

Abstract

2020 will be remembered worldwide for the outbreak of Coronavirus disease (COVID-19), which quickly spread until it was declared as a global pandemic. The main protease (Mpro) of SARS-CoV-2, a key enzyme in coronavirus, represents an attractive pharmacological target for inhibition of SARS-CoV-2 replication. Here, we evaluated whether the anti-inflammatory drug Ibuprofen, may act as a potential SARS-CoV-2 Mpro inhibitor, using an in silico study. From molecular dynamics (MD) simulations, we also evaluated the influence of ionic strength on the affinity and stability of the Ibuprofen-Mpro complexes. The docking analysis shows that R(À)Ibuprofen and S(þ)Ibuprofen isomers can interact with multiple key residues of the main protease, through hydrophobic interactions and hydrogen bonds, with favourable binding energies (À6.2 and À5.7 kcal/mol, respectively). MM-GBSA and MM-PBSA calculations confirm the affinity of these complexes, in terms of binding energies. It also demonstrates that the ionic strength modifies significantly their binding affinities. Different structural parameters calculated from the MD simulations (120 ns) reveal that these complexes are conformational stable in the different conditions analysed. In this context, the results suggest that the condition 2 (0.25 NaCl) bind more tightly the Ibuprofen to Mpro than the others conditions. From the frustration analysis, we could characterize two important regions (Cys44-Pro52 and Linker loop) of this protein involved in the interaction with Ibuprofen. In conclusion, our findings allow us to propose that racemic mixtures of the Ibuprofen enantiomers might be a potential treatment option against SARS-CoV-2 Mpro. However, further research is necessary to determinate their possible medicinal use.

Design and Evaluation of Bispidine-Based SARS-CoV-2 Main Protease Inhibitors

“…Validation of the system developed by us was performed using the drugs disulfiram and ebselen for comparison. The activity of these substances correlates with previously published data in the literature. , In addition, based on previously published theoretical calculations, we used ibuprofen as a reference drug. This compound showed no activity at all against the main protease.…”

Safety and Efficacy of Nebulised Anti-Inflammatory Solution of Alkaline Hypertonic Ibuprofen (AHI) for Treatment of SARS-Cov-2 Infection: A Compassionate Study with a Comparator Arms

“…In other "in vitro" studies it was demonstrated that Ibuprofen shows bactericidal and virucidal activity [26,27]. Through computational studies, it was recently suggested that Ibuprofen could interact with M-pro, the major protease present in Coronavirus [28].…”

Interplay between Inhaled Ibuprofenate, SARS-CoV-2, Vasoplegic Pulmonary Vascular Dysfunction, Pneumonia and CARDS

“…SARS-CoV-2 uses the host cellular interactome for its replication. NaIHS inhibits in silico [23] and may inhibit in vitro [24,25] the SARS-CoV-2 main protease (Mpro).…”

“…Cathepsin L: negative modulation by the inhibition of IL-6 [8] and the inhibition of the positive feedback loop among IL-6 [8], NF-kB [8] and STAT3 [8]; 7. Mpro inhibition in silico [23] and in vitro [24,25]; 8. Inhibition in silico of the proviral-factors: TYMP, PTGS2, C1S, CFB, IFI44, XAF1, CXCL2 and CXCL3 [26].…”

“…Inhibition of cathepsin L [8]; 7. Inhibition of Mpro in silico [23] and in vitro [24,25]; 8. Inhibition of the pro-viral factors TYMP, PTGS2, CIS, CFB, IFI44, CXCL2 and CXCL3 [26].…”