Evaluating therapeutic potential of AYUSH-64 constituents against omicron variant of SARS-CoV-2 using ensemble docking and simulations

Abstract

The COVID-19 pandemic in the later phase showed the presence of the B.1.1.529 variant of the SARS-CoV-2 designated as Omicron. AYUSH-64 a poly herbal drug developed by Central Council for Research in Ayurvedic Sciences (CCRAS) has been recommended by Ministry of Ayush in asymptomatic, mild to moderate COVID-19 patients. One of the earlier, in-silico study has shown the binding of the constituents of AYUSH-64 to the main protease (M^pro) of the SARS-CoV-2. This study enlisted four phytochemicals of AYUSH-64, which were found to have significant binding with the M^pro. In continuation to the same, the current study proposes to understand the binding of these four phytochemicals to main protease (M^pro) and receptor binding domain (RBD) of spike protein of the Omicron variant. An enhanced molecular docking methodology, namely, ensemble docking has been used to find the most efficiently binding phytochemical. Using molecular dynamics (MD) simulations and clustering approach it was observed that the M^pro and RBD Spike of Omicron variant of SARS-CoV-2 in complex with human ACE2 tends to attain 4 and 8 conformational respectively. Based on the docking studies, the best binding phytochemical of the AYUSH-64, akummicine N-oxide was selected for MD simulations. MD simulations of akummicine N-oxide bound to omicron variant of M^pro and RBD Spike-ACE complex was performed. The conformational, interaction and binding energy analysis suggested that the akummicine N-oxide binds well with M^pro and RBD Spike-ACE2 complex. The interaction between RBD Spike and ACE2 was observed to weaken in the presence of akummicine N-oxide. Hence, it can be inferred that, these phytochemicals from AYUSH-64 formulation may have the potential to act against the Omicron variant of SARS-CoV-2.

Keywords: Ayurveda; Ayush64; Ensemble docking; MD simulations; Phytochemicals.

Graphical abstract

Fig. 1

(A) Main protease (M^pro) and (B) receptor binding domain (RBD) of spike protein from the Omicron variant of SARS-CoV-2.

Fig. 2

Phytochemicals with their PubChem CIDs from the AYUSH-64 formulation that have been considered for the molecular docking study.

Fig. 3

Detailed outline of the methodology followed for ensemble docking of M^pro and RBD Spike-ACE2 systems.

Fig. 4

Comparison between the (A) mutant and (B–E) different Ereps of the Omicron variant of M^pro and wild type (PDB ID: 6LU7). (Inset table) The all atom RMSD between the representatives and the wild type M^pro.

Fig. 5

Comparison between the (A) mutant and (B–I) different Ereps of the Omicron variant of RBD Spike-ACE2 complex and wild type (PDB ID: 6LZG). (Inset table) The all atom RMSD between the representatives and the wild type RBD Spike-ACE2 complex.

Fig. 6

(A) Grid scores obtained through docking for the best phytochemicals in each ensemble representative and (B) binding of phytochemicals in wild type, mutant and ensemble states for M^pro.

Fig. 7

(A) Grid scores obtained through docking for the best phytochemicals in each ensemble representative and (B) binding of phytochemicals in wild type, mutant and ensemble states for RBD Spike-ACE2 complex.

Fig. 8

(A) Distribution of conformers along the RMSD of M^pro for M^pro-Apo and M^pro-Aku complex. (B–C) Secondary structure changes along the simulations of M^pro-Apo and M^pro-Aku simulations, respectively.

Fig. 9

RMSF for residues of M^pro from M^pro-Apo and M^pro-Aku systems along principal component (A) 1 and (B) 2. Projections of variance for the M^pro in systems (C) M^pro-Apo and (D) M^pro-Aku along PC1.

Fig. 10

Distribution of conformers along the RMSD of (A) RBD Spike-ACE2 complex, (B) RBD Spike and (C) ACE2 in SA-Apo and SA-Aku simulation systems.

Fig. 11

(A–B) RMSF for the residues of RBD Spike in the SA-Apo (black) and SA-Aku (red) systems along PC1 and PC2, respectively. (C–D) RMSF for the residues of ACE2 in the SA-Apo (black) and SA-Aku (red) systems along PC1 and PC2, respectively. (E–F) Projections of PC1 variation on the RBD Spike-ACE2 complex for the SA-Apo and SA-Aku systems, respectively. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 12

Residues interacting with akummicine N-oxide in the M^pro-Aku simulation system.

Fig. 13

Free energy of binding (ΔΔG_bind) between M^pro and Akummicine N-oxide throughout the simulations.

Fig. 14

Interactions between RBD Spike-ACE2 that were (A) lost and (B) gained in the SA-Aku simulation system. (C) ΔΔGbind between RBD Spike and ACE2 receptors in the SA-Apo (black) and SA-Aku (red) simulation systems. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 15

(A) Residues from RBD Spike-ACE2 complex interacting with akummicine N-oxide. (B) ΔΔG_bind between akummicine N-oxide and RBD Spike-ACE2 complex.