An Analysis Based on Molecular Docking and Molecular Dynamics Simulation Study of Bromelain as Anti-SARS-CoV-2 Variants

Abstract

The rapid spread of a novel coronavirus known as SARS-CoV-2 has compelled the entire world to seek ways to weaken this virus, prevent its spread and also eliminate it. However, no drug has been approved to treat COVID-19. Furthermore, the receptor-binding domain (RBD) on this viral spike protein, as well as several other important parts of this virus, have recently undergone mutations, resulting in new virus variants. While no treatment is currently available, a naturally derived molecule with known antiviral properties could be used as a potential treatment. Bromelain is an enzyme found in the fruit and stem of pineapples. This substance has been shown to have a broad antiviral activity. In this article, we analyse the ability of bromelain to counteract various variants of the SARS-CoV-2 by targeting bromelain binding on the side of this viral interaction with human angiotensin-converting enzyme 2 (hACE2) using molecular docking and molecular dynamics simulation approaches. We have succeeded in making three-dimensional configurations of various RBD variants using protein modelling. Bromelain exhibited good binding affinity toward various variants of RBDs and binds right at the binding site between RBDs and hACE2. This result is also presented in the modelling between Bromelain, RBD, and hACE2. The molecular dynamics (MD) simulations study revealed significant stability of the bromelain and RBD proteins separately up to 100 ns with an RMSD value of 2 Å. Furthermore, despite increases in RMSD and changes in Rog values of complexes, which are likely due to some destabilized interactions between bromelain and RBD proteins, two proteins in each complex remained bonded, and the site where the two proteins bind remained unchanged. This finding indicated that bromelain could have an inhibitory effect on different SARS-CoV-2 variants, paving the way for a new SARS-CoV-2 inhibitor drug. However, more in vitro and in vivo research on this potential mechanism of action is required.

Beneficial Properties of Bromelain

“…Tallei et al [229], for the first time, applied molecular docking and molecular dynamics simulation approaches to investigate the ability of bromelain to counteract various variants of the SARS-CoV-2 by targeting bromelain binding on the side of this viral interaction with angiotensin converting enzyme 2 (ACE2). The researchers found that bromelain exhibited good binding affinity toward various variants of the receptor-binding domain (RBD) responsible for the attachment of the virus to ACE2.…”

Fruit Bromelain-Derived Peptide Potentially Restrains the Attachment of SARS-CoV-2 Variants to hACE2: A Pharmacoinformatics Approach

“…When compared to bromelain, the binding position of bromelain-derived peptide is generally similar, namely at the hACE2-RBD binding site. This is demonstrated by the similarity of the interacting amino acids between RBD WT and variants and these two molecules, particularly the critical residues Phe486, Gln493, and Asn501 [ 27 ].…”

“…According to our previous in silico research, bromelain has a high binding affinity for various RBD variants and binds directly at the binding site between RBDs and hACE2. This suggests that bromelain has the potential to inhibit SARS-CoV-2 attachment to hACE2 [ 27 ]. In one study, the bromelain peptide biomarker DYGAVNEVK was found in the plasma of bromelain-treated mice.…”

Plant cysteine proteases: Potential therapeutic agents against SARS‐CoV‐2

“…BromAc also induced the unfolding of recombinant spike and envelope proteins by reducing disulfide stabilizer bridges and inhibited the replication of wild-type and spike mutant SARS-CoV-2 (Akhter et al, 2021). Moreover, in an in silico study, Tallei et al (2021) suggests that bromelain effectively binds to receptor-binding domain (RBD)'s active site of spike glycoprotein and also could have an inhibitory effect on different SARS-CoV-2 variants. This result is encouraging, given the number of SARS-CoV-2 variants that have been identified.…”

“…The proteinases found in pineapple include fruit bromelain (EC 3.4.22.33), stem bromelain (EC 3.4.22.32),and ananain (EC 3.4.22.31). Bromelain has proven therapeutic properties, for example, antiinflammatory, anticoagulant, anthelminthic, antimicrobial, and immunomodulatory effects (Chakraborty et al, 2021;Kritis, Karampela, Kokoris, & Dalamaga, 2020;Tallei et al, 2021). Here, we will emphasize its antiviral effect, particularly anti-SARS-CoV-2.…”