In silico evaluation of the compounds of the ayurvedic drug, AYUSH-64, for the action against the SARS-CoV-2 main protease

Abstract

Background: Outbreak of Corona Virus Disease in late 2019 (COVID-19) has become a pandemic global Public health emergency. Since there is no approved anti-viral drug or vaccine declared for the disease and investigating existing drugs against the COVID-19.

Objective: AYUSH-64 is an Ayurvedic formulation, developed and patented by Central Council of Research in Ayurvedic Sciences, India, has been in clinical use as anti-malarial, anti-inflammatory, anti-pyretic drug for few decades. Thus, the present study was undertaken to evaluate AYUSH-64 compounds available in this drug against Severe Acute Respiratory Syndrome-Corona Virus (SARS-CoV-2) Main Protease (M^pro; PDB ID: 6LU7) via in silico techniques.

Materials and methods: Different molecular docking software's of Discovery studio and Auto Dock Vina were used for drugs from selected AYUSH-64 compounds against SARS-CoV-2. We also conducted 100 ns period of molecular dynamics simulations with Desmond and further MM/GBSA for the best complex of AYUSH-64 with M^pro of SARS-CoV-2.

Results: Among 36 compounds of four ingredients of AYUSH-64 screened, 35 observed to exhibits good binding energies than the published positive co-crystal compound of N3 pepetide. The best affinity and interactions of Akuammicine N-Oxide (from Alstonia scholaris) towards the M^pro with binding energy (AutoDock Vina) of -8.4 kcal/mol and Discovery studio of Libdock score of 147.92 kcal/mol. Further, molecular dynamics simulations with MM-GBSA were also performed for M^pro- Akuammicine N-Oxide docked complex to identify the stability, specific interaction between the enzyme and the ligand. Akuammicine N-Oxide is strongly formed h-bonds with crucial M^pro residues, Cys145, and His164.

Conclusion: The results provide lead that, the presence of M^pro- Akuammicine N-Oxide with highest M^pro binding energy along with other 34 chemical compounds having similar activity as part of AYUSH-64 make it a suitable candidate for repurposing to management of COVID-19 by further validating through experimental, clinical studies.

Keywords: AYUSH-64; COVID-19; Dynamics simulations; Main protease; Molecular docking; SARS-CoV-2.

Graphical abstract

Fig. 1

Superimposition of the docked M^pro– N3 peptide with its X-ray crystal structure. A) Blue and yellow color indicates experimentally derived structure of M^pro– N3 peptide, the docked complex of orange – brown and green – yellow orange is derived from Discovery studio and Autodock Vina docking approaches respectively. B) 2D interaction of experimental and docked M^pro of SARS- CoV-2.

Fig. 2

Molecular docking score of AYUSH-64 compounds. Among Akuammicine N-Oxide (green) has least docking sore of -8.4 kcal/mol and N3 peptide (red) has docking sore -4.1 kcal/mol.

Fig. 3

A) Molecular interactions of Akuammicine N-Oxide with 2019-nCoV of M^pro. B) 2D interaction of docked M^pro of SARS- CoV-2 with Akuammicine N-Oxide.

Fig. 4

The stable total energy, potential energy, temperature, pressure and volume of molecular dynamics simulations at 100 ns period of 2019-nCoV M^pro with Akuammicine N-Oxide(A) and N3 peptide (B).

Fig. 5

RMSD of protein Cα atoms of SARS-COv-2 M^pro (pink)and compounds (grayish green) during 100 ns of MD simulation. (A) M^pro– Akuammicine compex (B) M^pro– N-Oxide and N3 pepeide complex.

Fig. 6

RMSF of M^pro (Blue) and sidechain of (brown) are forms H-bond interactions (green line) with Akuammicine N-Oxide. (A) Docked copmex (B) Native complex.

Fig. 7

Post molecular dynamics simulations of (A) Akuammicine N-Oxideand (B) N3 peptide were formed interactions with M^pro of SARS-CoV-2.