Cordifolioside: potent inhibitor against Mpro of SARS-CoV-2 and immunomodulatory through human TGF-β and TNF-α

Abstract

Therapeutic options for SARS-CoV-2 are limited merely to the symptoms or repurposed drugs and non-specific interventions to promote the human immune system. In the present study, chromatographic and in silico approaches were implemented to identify bioactive compounds which might play pivotal role as inhibitor for SARS-CoV-2 and human immunomodulator (TGF-β and TNF-α). Tinospora cordifolia (Willd.) Miers was evaluated for phenolic composition and explored for bioactive compounds by high-performance thin layer chromatography (HPTLC). Furthermore, the bioactive compounds such as cordifolioside, berberine, and magnoflorine were appraised as human immunomodulatory and potent inhibitor against Main Protease (M^pro) of SARS-CoV-2 through multiple docking strategies. Cordifolioside formed six stable H-bonds with His41, Ser144, Cys145, His163, His164, and Glu166 of M^pro of SARS-CoV-2, which displayed a significant role in the viral replication/transcription during infection acting towards the common conserved binding cleft among all strains of coronavirus. Overall, the study emphasized that the proposed cordifolioside might use for future investigations, which hold as a promising scaffold for developing anti-COVID-19 drug and reduce human cytokine storm.

Keywords: COVID-19; Dynamics simulations; HPTLC; Main protease; Molecular docking; SARS-CoV-2; Sequence analysis; Tinospora cordifolia.

Fig. 1

HPTLC chromatogram of T. cordifolia extracts and standards; cordifolioside, magnoflorine, and berberine

Fig. 2

Phylogenetic tree analysis of the corona family. The M^pro of SARS-CoV-2 evolutionary associated with SARS-CoV and distantly related to H-CoV-229E

Fig. 3

Conserved M^pro-binding site analysis (red-colored box) in the corona family. The residues of His41, Phe140, Cys145, Gly146, His164, Glu166, and His172 have 100% identity with the family of corona and Ile141, Ser144, and Met163 has physicochemically similar

Fig. 4

Molecular interactions of the native and docked complex of M^pro with N3 peptide by the Discovery Studio of LibDock. a The native co-crystal structure of M^pro (pink) with N3 peptide (blue) and docked structure of M^pro (green) with N3 peptide (red) showed RMSD with 1.53 Å. b Interactions of docked N3 peptide within 4 Ȧ of M^pro

Fig. 5

Molecular interactions of the native and docked complex of M^pro with N3 peptide by the AutoDock Vina. a The native complex of M^pro (pink) with N3 peptide (blue) has RMSD of 1.84 Å when associated with the docked complex of M^pro(cyan) with N3 peptide (orange). b Interactions of docked N3 peptide within 4 Ȧ of M^pro

Fig. 6

Molecular interaction of cordifolioside (purple), berberine (red), and magnoflorine (blue) with M^pro of SARS-CoV-2

Fig. 7

RMSD of Cα-atoms of M^pro (greenish-blue) with cordifolioside (pink) complex at 100 ns molecular simulations run

Fig. 8

RMSF of M^pro of Cα-atoms and side-chain with binding site residues (green) at 100 ns molecular simulations run

Fig. 9

Binding site residues of SARS-CoV-2 M^pro displaying H-bonds, Hydrophobic, Ionic, and water-associated interactions with cordifolioside

Fig. 10

Cordifolioside properties of average a rGyr: 4.9, b MolSA: 446.9, c SASA: 243.4 and d PSA: 326.9 were stable at MD simulation at 100 ns simualtions

Fig. 11

Depiction of cordifolioside and M^pro SARS-CoV-2 complex involved in torsion angle graph plotted at 100 ns simulation time

Fig. 12

Binding modes and molecular interactions of T. cordifolia selected compounds with anti-inflammatory biomarkers of TGF-β (1PY5) by a molecular docking simulation study

Fig. 13

Binding mode and interactive residues of T. cordifolia selected compound with a pro-inflammatory biomarker of TNF-α (6OP0) obtained by molecular docking simulation