Caffeic acid derivatives (CAFDs) as inhibitors of SARS-CoV-2: CAFDs-based functional foods as a potential alternative approach to combat COVID-19

Abstract

Background: SARS-CoV-2, an emerging strain of coronavirus, has affected millions of people from all the continents of world and received worldwide attention. This emerging health crisis calls for the urgent development of specific therapeutics against COVID-19 to potentially reduce the burden of this emerging pandemic.

Purpose: This study aims to evaluate the anti-viral efficacy of natural bioactive entities against COVID-19 via molecular docking and molecular dynamics simulation.

Methods: A library of 27 caffeic-acid derivatives was screened against 5 proteins of SARS-CoV-2 by using Molegro Virtual Docker 7 to obtain the binding energies and interactions between compounds and SARS-CoV-2 proteins. ADME properties and toxicity profiles were investigated via www.swissadme.ch web tools and Toxtree respectively. Molecular dynamics simulation was performed to determine the stability of the lead-protein interactions.

Results: Our obtained results has uncovered khainaoside C, 6-O-Caffeoylarbutin, khainaoside B, khainaoside C and vitexfolin A as potent modulators of COVID-19 possessing more binding energies than nelfinavir against COVID-19 M^pro, Nsp15, SARS-CoV-2 spike S2 subunit, spike open state and closed state structure respectively. While Calceolarioside B was identified as pan inhibitor, showing strong molecular interactions with all proteins except SARS-CoV-2 spike glycoprotein closed state. The results are supported by 20 ns molecular dynamics simulations of the best complexes.

Conclusion: This study will hopefully pave a way for development of phytonutrients-based antiviral therapeutic for treatment or prevention of COVID-19 and further studies are recommended to evaluate the antiviral effects of these phytochemicals against SARS-CoV-2 in in vitro and in vivo models.

Keywords: Bioactive phytochemicals; COVID-19; Caffeic acid derivative; SARS-CoV-2.

Graphical abstract

Fig. 1

Chemical structures of caffeic acid and its derivatives.

Fig. 2

Docking poses of caffeic acid derivatives with COVID-19 virus M^pro(A) Hydrogen bonding interactions of khaınaosıde C, scrophuloside B, vitexfolin A, calceolarioside B and calceolarioside C with amino acid residues of COVID-19 virus M^pro, (B) 2D view of interaction types of khaınaosıde C, scrophuloside B, vitexfolin A, calceolarioside B and calceolarioside C with surrounding amino acids of COVID-19 virus M^pro.

Fig. 3

Docking poses of caffeic acid derivatives with COVID-19 virus Nsp15 endoribonuclease (A) Hydrogen bonding interactions of 6-O-Caffeoylarbutin, calceolarioside B, dodegranoside A, calceolarioside A and scrophuloside B with amino acid residues of virus Nsp15 endoribonuclease (B) 2D view of interaction types of 6-O-Caffeoylarbutin, calceolarioside B, dodegranoside A, calceolarioside A and scrophuloside B with surrounding amino acids of COVID-19 virus Nsp15 endoribonuclease.

Fig. 4

Docking poses of caffeic acid derivatives with COVID-19 virus fusion protein S2 subunit (A) Hydrogen bonding interactions of khaınaosıde B, chicoric acid, vitexfolin A, 6-O-Caffeoylarbutin, and calceolarioside B with amino acid residues of fusion protein S2 subunit (B) 2D view of interaction types of khaınaosıde B, chicoric acid, vitexfolin A, 6-O-Caffeoylarbutin, and calceolarioside B with surrounding amino acids of COVID-19 virus fusion protein S2 subunit.

Fig. 5

Docking poses of caffeic acid derivatives with SARS-CoV-2 spike ectodomain (A) Hydrogen bonding interactions of khaınaosıde C, khaınaosıde B, calceolarioside B, calceolarioside C, calceolarioside D with amino acid residues of SARS-CoV-2 spike ectodomain (open state) (B) 2D view of interaction types of khaınaosıde C, khaınaosıde B, calceolarioside B, calceolarioside C, calceolarioside D with surrounding amino acids of SARS-CoV-2 spike ectodomain (open state).

Fig. 6

Docking poses of caffeic acid derivatives with SARS-CoV-2 spike glycoprotein (closed state) (A) Hydrogen bonding interactions of scrophuloside B, chicoric acid, vitexfolin A, cynarin and eutıgosıde A with amino acid residues of SARS-CoV-2 spike glycoprotein (closed state) (B) 2D view of interaction types of scrophuloside B, chicoric acid, vitexfolin A, cynarin and eutıgosıde A with surrounding amino acids of spike glycoprotein (closed state).

Fig. 7

MolDock Score comparison among 27 compounds versus active sites SARS-CoV-2 6LU7, 6VWW, 6LXT, 6VYB, and 6VXX.

Fig. 8

Bioavailability Radar related to physicochemical properties of molecules (Criterias: Lipophilicity: - 0.7 < XLOGP3 < ++5.0, Size: 150 MW 500 g/mol, Polarity: 20 < TPSA < 130 Å2, Insolubility: 0 < log S < 6, Insaturation, Flexibility: 0.25 < rotatable bonds < 9).

Fig. 9

Post-dynamics analysis: (A) Root Mean Square Deviation (RMSD) (blue line), Radius of Gyration (RoG) (orange line), and surface accessible surface area (SASA) (gray line) for the best complex for each viral protein during 20 ns MDS run. (B) Per-residue Root Mean Square Fluctuation (RMSF) for the same complexes with dashed lines represents the active residues. (C) Post-dynamics average binding energies (in kcal/mol) calculated for the complexes using AutoDock Vina. Error bars represent the standard deviations.