Evaluation of the active constituents of Nilavembu Kudineer for viral replication inhibition against SARS-CoV-2: An approach to targeting RNA-dependent RNA polymerase (RdRp)

Abstract

The World Health Organization has declared the novel coronavirus (COVID-19) outbreak a global pandemic and emerging threat to people in the 21st century. SARS-CoV-2 constitutes RNA-Dependent RNA Polymerase (RdRp) viral proteins, a critical target in the viral replication process. No FDA-approved drug is currently available, and there is a high demand for therapeutic strategies against COVID-19. In search of the anti-COVID-19 compound from traditional medicine, we evaluated the active moieties from Nilavembu Kudineer (NK), a poly-herbal Siddha formulation recommended by AYUSH against COVID-19. We conducted a preliminary docking analysis of 355 phytochemicals (retrieved from PubChem and IMPPAT databases) present in NK against RdRp viral protein (PDB ID: 7B3B) using COVID-19 Docking Server and further with AutoDockTool-1.5.6. MD simulation studies confirmed that Orientin (L1), Vitexin (L2), and Kasuagamycin (L3) revealed better binding activity against RdRp (PDB ID: 7B3B) in comparison with Remdesivir. The study suggests a potential scaffold for developing drug candidates against COVID-19. PRACTICAL APPLICATIONS: Nilavembu Kudineer is a poly-herbal Siddha formulation effective against various diseases like cough, fever, breathing problems, etc. This study shows that different phytoconstituents identified from Nilavembu Kudineer were subjected to in silico and ADME analyses. Out of the former 355 phytochemical molecules, Orientin (L1), Vitexin (L2), and Kasuagamycin (L3) showed better binding activity against RdRp viral protein (PDB ID: 7B3B) in comparison with the synthetic repurposed drug. Our work explores the search for an anti-COVID-19 compound from traditional medicine like Nilavembu Kudineer, which can be a potential scaffold for developing drug candidates against COVID-19.

Keywords: Nilavembu Kudineer; COVID-19; RNA-dependent RNA polymerase; SARS-CoV-2; traditional medicine.

FIGURE 1

Some active site residues of RdRp protein (a). The molecular docking interaction networks of L1‐bound RdRp (d), L2‐bound RdRp (b), and L3‐bound RdRp (c).

FIGURE 2

(Color online) Structure of L1‐RdRp at 40 ns (a). Visual illustration of the interaction options in the L1‐RdRp system (b). Per‐residue energy contributions of the RdRp interacting residues (c).

FIGURE 3

(Color online) Structure of L2‐RdRp at 40 ns (a). Visual illustration of the interaction options in the L2‐RdRp system (b). Per‐residue energy contributions of the RdRp interacting residues (c).

FIGURE 4

(Color online) Structure of L3‐RdRp at 40 ns (a). Visual illustration of the interaction options in the L3‐RdRp system (b). Per‐residue energy contributions of the RdRp interacting residues (c).

FIGURE 5

The RMSD, RMSF, and RoG plot C‐α atoms of the bound and unbound protein systems. (a) The superimposed structures of L1‐RdRp, L2‐RdRp, and L3‐RdRp. (b) RMSD, (c) RMSF, and (d) RoG plots for ApoRdRp (black), L1‐RdRp (red), L2‐RdRp (blue), and L3‐RdRp (green).

FIGURE 6

demonstrates the lentiviral particle count on HEK293T‐hACE2 cells upon 48 hr treatment with chloroquine (62.51 μM) and Vitexin (46.25 μM).