Luteolin and abyssinone II as potential inhibitors of SARS-CoV-2: an in silico molecular modeling approach in battling the COVID-19 outbreak

Abstract

Background: At present, the entire world is in a war against COVID-19 pandemic which has gradually led us toward a more compromised "new normal" life. SARS-CoV-2, the pathogenic microorganism liable for the recent COVID-19 outbreak, is extremely contagious in nature resulting in an unusual number of infections and death globally. The lack of clinically proven therapeutic intervention for COVID-19 has dragged the world's healthcare system into the biggest challenge. Therefore, development of an efficient treatment scheme is now in great demand. Screening of different biologically active plant-based natural compounds could be a useful strategy for combating this pandemic. In the present research, a collection of 43 flavonoids of 7 different classes with previously recorded antiviral activity was evaluated via computational and bioinformatics tools for their impeding capacity against SARS-CoV-2. In silico drug likeness, pharmacophore and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) profile analysis of the finest ligands were carried out using DataWarrior, DruLiTo and admetSAR programs, respectively. Molecular docking was executed by AutoDock Vina, while molecular dynamics simulation of the target protein-ligand bound complexes was done using nanoscalable molecular dynamics and visual molecular dynamics software package. Finally, the molecular target analysis of the selected ligands within Homo sapiens was conducted with SwissTargetPredcition web server.

Results: Out of the forty-three flavonoids, luteolin and abyssinone II were found to develop successful docked complex within the binding sites of target proteins in terms of lowest binding free energy and inhibition constant. The root mean square deviation and root mean square fluctuation values of the docked complex displayed stable interaction and efficient binding between the ligands and target proteins. Both of the flavonoids were found to be safe for human use and possessed good drug likeness properties and target accuracy.

Conclusions: Conclusively, the current study proposes that luteolin and abyssinone II might act as potential therapeutic candidates for SARS-CoV-2 infection. In vivo and in vitro experiments, however, should be taken under consideration to determine the efficiency and to demonstrate the mechanism of action.

Keywords: Abyssinone II; COVID-19 pandemic; Flavonoids; Luteolin; Molecular docking; Molecular dynamics simulation; SARS-CoV-2.

Fig. 1

The complete workflow for the identification of luteolin and abyssinone II as most potent inhibitors against Mpro/3CLro, PLpro and ACE2 of COVID-19

Fig. 2

a 2D structure of C3/luteolin, b 3D structure of C3/luteolin, c 2D structure of C43/abyssinone II and d 3D structure of C43/abyssinone II

Fig. 3

Binding poses (within the active site) and molecular interaction between C3/luteolin and different targets of COVID-19. a1, a2 C3/luteolin and Mpro/3CLpro, b1, b2 C3/luteolin and PLpro and c1, c2 C3/luteolin and ACE2. Inside the active site, targets are illustrated as solid ribbon and the bound ligands as stick. The molecular interactions are represented by the green dashed lines for hydrogen bonds and semi-arcs with red eyelashes for hydrophobic interactions

Fig. 4

Binding poses (within the active site) and molecular interaction between C43/abyssinone II and different targets of COVID-19. a1, a2 C43/abyssinone II and Mpro/3CLpro, b1, b2 C43/abyssinone II and PLpro and c1, c2 C43/abyssinone II and ACE2. Inside the active site, targets are illustrated as solid ribbon and the bound ligands as stick. The molecular interactions are represented by the green dashed lines for hydrogen bonds and semi-arcs with red eyelashes for hydrophobic interactions

Fig. 5

Binding poses (within the active site) and molecular interaction between Con-2/remdesivir and different targets of COVID-19. a1, a2 Con-2/remdesivir and Mpro/3CLpro, b1, b2 Con-2/remdesivir and PLpro and c1, c2 Con-2/remdesivir and ACE2. Inside the active site, targets are illustrated as solid ribbon and the bound ligands as stick. The molecular interactions are represented by the green dashed lines for hydrogen bonds and semi-arcs with red eyelashes for hydrophobic interactions

Fig. 6

a RMSD plot of 5 ns MD simulation for free and bound Mpro/3CLpro complexed with C3/luteolin, C43/abyssinone II and Con-2/remdesivir, b RMSF plot of free and bound Mpro/3CLpro complexed with C3/luteolin, C43/abyssinone II and Con-2/remdesivir

Fig. 7

a RMSD plot of 5 ns MD simulation for free and bound PLpro complexed with C3/luteolin, C43/abyssinone II and Con-2/remdesivir, b RMSF plot of free and bound PLpro complexed with C3/luteolin, C43/abyssinone II and Con-2/remdesivir

Fig. 8

a RMSD plot of 5 ns MD simulation for free and bound ACE2 complexed with C3/luteolin, C43/abyssinone II and Con-2/remdesivir, b RMSF plot of free and bound ACE2 complexed with C3/luteolin, C43/abyssinone II and Con-2/remdesivir

Fig. 9

Top 25 classes of molecular targets within H. sapiens predicted for a C3/luteolin and b C43/abyssinone II