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. 2021 Oct;39(16):6218-6230.
doi: 10.1080/07391102.2020.1794972. Epub 2020 Jul 21.

Cyanobacterial metabolites as promising drug leads against the Mpro and PLpro of SARS-CoV-2: an in silico analysis

Devashan Naidoo  1 , Ayan Roy  2 , Pallab Kar  3 , Taurai Mutanda  1 , Akash Anandraj  1
Affiliations

Cyanobacterial metabolites as promising drug leads against the Mpro and PLpro of SARS-CoV-2: an in silico analysis

Devashan Naidoo et al. J Biomol Struct Dyn. 2021 Oct.

Abstract

A novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has emerged as the causative agent behind the coronavirus disease 2019 (COVID-19) pandemic. Treatment efforts have been severely impeded due to the lack of specific effective antiviral drugs for the treatment of COVID-associated pathologies. In the present research endeavour the inhibitory prospects of cyanobacterial metabolites were assessed at the active binding pockets of the two vital SARS-CoV-2 proteases namely, main protease (Mpro) and the papain-like protease (PLpro) that proteolytically process viral polyproteins and facilitate viral replication, employing an in silico molecular interaction-based approach. It was evident from our analysis based on the binding energy scores that the metabolites cylindrospermopsin, deoxycylindrospermopsin, carrageenan, cryptophycin 52, eucapsitrione, tjipanazole, tolyporphin and apratoxin A exhibited promising inhibitory potential against the SARS-CoV-2 Mpro. The compounds cryptophycin 1, cryptophycin 52 and deoxycylindrospermopsin were observed to display encouraging binding energy scores with the PLpro of SARS-CoV-2. Subsequent estimation of physicochemical properties and potential toxicity of the metabolites followed by robust molecular dynamics simulations and analysis of MM-PBSA energy scoring function established deoxycylindrospermopsin as the most promising inhibitory candidate against both SARS-CoV-2 proteases. Present research findings bestow ample scopes to further exploit the potential of deoxycylindrospermopsin as a successful inhibitor of SARS-CoV-2 in vitro and in vivo and pave the foundation for the development of novel effective therapeutics against COVID-19.Communicated by Ramaswamy H. Sarma.

Keywords: MM-PBSA; SARS-CoV-2; cyanobacterial metabolites; deoxycylindrospermopsin; drug-likeness; molecular docking; molecular dynamics simulations.

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Conflict of interest statement

The authors wish to declare that there are no conflicts of interest.

Figures

Figure 1.
Figure 1.
The structure of the cyanobacterial metabolites investigated for their ability to interact with the Mpro and PLpro of SARS-CoV-2.
Figure 1.
Figure 1.
The structure of the cyanobacterial metabolites investigated for their ability to interact with the Mpro and PLpro of SARS-CoV-2.
Figure 2.
Figure 2.
Mode of interaction of deoxycylindrospermopsin with SARS-CoV-2 Mpro. Cyan sphere represents SARS-CoV-2 Mpro. Orange sphere represents deoxycylindrospermopsin. Hydrophobic interactions have been represented as grey dashed lines and hydrogen bonds have been displayed as blue lines. Salt bridges have been represented as yellow dashed lines.
Figure 3.
Figure 3.
Mode of interaction of deoxycylindrospermopsin with SARS-CoV-2 PLpro. Blue sphere represents theSARS-CoV-2 PLpro. Orange sphere represents deoxycylindrospermopsin. Hydrophobic interactions have been represented as grey dashed lines and hydrogen bonds have been displayed as blue lines. Salt bridges have been represented as yellow dashed lines.
Figure 4.
Figure 4.
(A) RMSD analysis of the free receptor SARS-CoV-2 Mpro (green) and complex deoxycylindrospermopsin-CoV-2 Mpro (red) along a timescale of 120 ns (B) RMSD analysis of the free receptor SARS-CoV-2 PLpro (blue) and complex deoxycylindrospermopsin-SARS-CoV-2 PLpro (black) along a timescale of 120 ns.
Figure 5.
Figure 5.
(A) RMSF analysis of the free receptor SARS-CoV-2 Mpro (green) and complex deoxycylindrospermopsin-SARS-CoV-2 Mpro (red) along a timescale of 120 ns (B) RMSF analysis of the free receptor SARS-CoV-2 PLpro (blue) and complex deoxycylindrospermopsin-SARS-CoV-2 PLpro (black) along a timescale of 120 ns.
Figure 6.
Figure 6.
(A) Number of hydrogen bonds of the deoxycylindrospermopsin-SARS-CoV-2 Mpro complex (red) as a function of time during MD simulations of 120 ns. (B) Number of hydrogen bonds of the deoxycylindrospermopsin-SARS-CoV-2 PLpro complex (blue) as a function of time during MD simulations of 120 ns.
Figure 7.
Figure 7.
Interaction profile (Ligplot image) of (A) deoxycylindrospermopsin-SARS-CoV-2 Mpro complex after 120 ns MD simulations (B) deoxycylindrospermopsin-SARS-CoV-2 PLpro complex after 120 ns MD simulations. Hydrophobic and hydrogen bond interactions in the respective figures have been marked as red and green dashed lines respectively.
See this image and copyright information in PMC

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