DFT and MD simulation investigation of favipiravir as an emerging antiviral option against viral protease (3CLpro) of SARS-CoV-2

Abstract

As per date, around 20 million COVID-19 cases reported from across the globe due to a tiny 125 nm sized virus: SARS-CoV-2 which has created a pandemic and left an unforgettable impact on our world. Besides vaccine, medical community is in a race to identify an effective drug, which can fight against this disease effectively. Favipiravir (F) has recently attracted too much attention as an effective repurposed drug against COVID-19. In the present study, the pertinency of F has been tested as an antiviral option against viral protease (3CL^pro) of SARS-CoV-2 with the help of density functional theory (DFT) and MD Simulation. Different electronic properties of F such as atomic charges, molecular electrostatic properties (MEP), chemical reactivity and absorption analysis have been studied by DFT. In order to understand the interaction and stability of inhibitor F against viral protease, molecular docking and MD simulation have been performed. Various output like interaction energies, number of intermolecular hydrogen bonding, binding energy etc. have established the elucidate role of F for the management of CoV-2 virus for which there is no approved therapies till now. Our findings highlighted the need to further evaluate F as a potential antiviral against SARS-CoV-2.

Keywords: Density functional theory; Electronic properties; Favipiravir; Molecular docking; SARS-CoV-2.

Graphical abstract

Fig. 1

Structure of receptor protein (6LU7) [from Protein data bank] and F as ligand molecule [from Gauss view].

Fig. 2

Mulliken and natural charges distribution of the F.

Fig. 3

Molecular electrostatic potential map of the molecule F (Red colour; represent electron-rich sites, orange color; partially negative charge, yellow color; lightly electron-rich regions, blue; positive charge and green color; neutral sites).

Fig. 4

UV-visible spectra of F molecule computed by TD-DFT/6-311G*(d,p) method.

Fig. 5

(a) Binding energies F, (b) 3D view of Donor:acceptor surface for best pose in terms of H-bond interaction (c) 2D view of possible types of interaction in pose for F:6LU7 (Green: Conventional Hydrogen bond, Dark pink:π-π bond, sky blue: carbon hydrogen bond).

Fig. 6

Root mean square deviation (RMSD) graphs for apo state of receptor protein 6LU7 and in complex (Favipiravir:6LU7) with receptor protein 6LU7 up to 100 ns.

Fig. 7

(a) RMSF for apo state 6LU7 and of complex F:6LU7 structure, (b) R_g for apo state 6LU7 and of complex F:6LU7, structure in time trajectory (0–100 ns).

Fig. 8

(a): SASA area for protein 6LU7 in its apo state and for complex F:6LU7 structure and (b) Intermolecular hydrogen bond numbers for complex F:6LU7 structure for the total time trajectory, 0–100,000 ps.

Fig. 9

2D graph for F:6LU7complex:Variation of Coulombic interaction energy and Lenard Jones interaction energy with respect to whole time trajectory (0–100 ns).

Fig. 10

For F:6LU7 complex: (a) Variation of Coulombic interaction energy and Lenard Jones interaction energy with respect to time trajectory 0 –100 ns (b) attached with color contour representation with specific color coding.

Fig. 11

Variation of total binding energy for F with receptor protein in time trajectory 0–100 ns.

Fig. 12

(a) Structural position of first frame (0 ns) and last frame (100 ns), (b) Superposition of initial and final of F bound 3CL^pro complex after MD simulation.

Fig. 13

Projection of protein atoms in phase space along the first two principal eigenvectors. (a) protein 6LU7 (b) Protein complexed with standard protease inhibitor F(c) Superimposed plot showing Protein 6LU7 unbound protein and protein complexed with inhibitor F.

Fig. 14

Free energy landscape of the first principal components for (a) protein 6LU7 (b) Protein complexed with standard protease inhibitor F.