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. 2021 Jul 19:9:e11590.
doi: 10.7717/peerj.11590. eCollection 2021.

The impact of curcumin derived polyphenols on the structure and flexibility COVID-19 main protease binding pocket: a molecular dynamics simulation study

Aweke Mulu  1 , Mulugeta Gajaa  2 , Haregewoin Bezu Woldekidan  1 , Jerusalem Fekadu W/Mariam  1
Affiliations

The impact of curcumin derived polyphenols on the structure and flexibility COVID-19 main protease binding pocket: a molecular dynamics simulation study

Aweke Mulu et al. PeerJ. .

Abstract

The newly occurred SARS-CoV-2 caused a leading pandemic of coronavirus disease (COVID-19). Up to now it has infected more than one hundred sixty million and killed more than three million people according to 14 May 2021 World Health Organization report. So far, different types of studies have been conducted to develop an anti-viral drug for COVID-19 with no success yet. As part of this, silico were studied to discover and introduce COVID-19 antiviral drugs and results showed that protease inhibitors could be very effective in controlling. This study aims to investigate the binding affinity of three curcumin derived polyphenols against COVID-19 the main protease (Mpro), binding pocket, and identification of important residues for interaction. In this study, molecular modeling, auto-dock coupled with molecular dynamics simulations were performed to analyze the conformational, and stability of COVID-19 binding pocket with diferuloylmethane, demethoxycurcumin, and bisdemethoxycurcumin. All three compounds have shown binding affinity -39, -89 and -169.7, respectively. Demethoxycurcumin and bisdemethoxycurcumin showed an optimum binding affinity with target molecule and these could be one of potential ligands for COVID-19 therapy. And also, COVID-19 main protease binding pocket binds with the interface region by one hydrogen bond. Moreover, the MD simulation parameters indicated that demethoxycurcumin and bisdemethoxycurcumin were stable during the simulation run. These findings can be used as a baseline to develop therapeutics with curcumin derived polyphenols against COVID-19.

Keywords: Binding energy; Docking; NAMD; SARS-CoV-2; X-ray crustal structure.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1. Interactions of selected polyphenols and Main protease binding pocket residues.
For all polyphenols, carbon atoms are shown in black, oxygens in red, and nitrogens in blue. Bonds in the Diferuloylmethane, Demethoxycurcumin, and Bisdemethoxycurcumin are shown in purple, and bonds in binding pocket residues are in brown. Hydrogen bonds are shown (with their lengths) as green dashed lines. Residues making hydrophobic interactions with the Diferuloylmethane, Demethoxycurcumin, and Bisdemethoxycurcumin are shown as red arcs with radiating lines. Diferuloylmethane, Demethoxycurcumin, and Bisdemethoxycurcumin atoms involved in these hydrophobic interactions are shown with radiating red lines.
Figure 2
Figure 2. Plots of root-mean-square deviations of free SARS CoV-2 main protease (Mpro) (blue) and the complex of SARS CoV-2 main protease (7BUY) (red) with three polyphenols along the MD simulation time.
Free SARS CoV-2 main protease (Mpro) (blue) and the complex of SARS CoV-2 main protease (7BUY) (red) with three polyphenols.
Figure 3
Figure 3. Plots of Root-mean-square deviations of free main CoV-2 protease (Mpro) (gray) and the complex of Mpro with Bisdemethoxycurcumin (yellow), Demethoxycurcumin (blue) and Diferuloylmethane (red) along the MD simulation time for three individual polyphenols.
Free main CoV-2 protease (Mpro) (gray), the complex of Mpro with Bisdemethoxycurcumin (yellow), Demethoxycurcumin (blue) and Diferuloylmethane (red).
Figure 4
Figure 4. RMSF plot of free main CoV-2 protease (Mpro) (yellow) and the complex of Mpro with Bisdemethoxycurcumin (red), Demethoxycurcumin (blue) and Diferuloylmethane (gray) along the MD simulation time for three individual polyphenols.
Free main CoV-2 protease (Mpro) (yellow), the complex of Mpro with Bisdemethoxycurcumin (red), Demethoxycurcumin (Blue) and Diferuloylmethane (gray).
Figure 5
Figure 5. Number of hydrogen bond present in Bisdemethoxycurcumin-SARS-CoV-2 main protease (yellow), Demethoxycurcumin-SARS-CoV-2 main protease (gray), free SARS-CoV-2 main protease (red) and diferuloylmethane-main protease (blue).
Bisdemethoxycurcumin-SARS-CoV-2 main protease (yellow), Demethoxycurcumin-SARS-CoV-2 main protease (gray), free SARS-CoV-2 main protease (red) and diferuloylmethane-main protease (blue).
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Grants and funding

This work was supported by the University of Addis Ababa Science and Technology for using computational resources. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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