Uncaria tomentosa (cat's claw): a promising herbal medicine against SARS-CoV-2/ACE-2 junction and SARS-CoV-2 spike protein based on molecular modeling

Abstract

COVID-19 is a novel severe acute respiratory syndrome coronavirus. Currently, there is no effective treatment and vaccines seem to be the solution in the future. Virtual screening of potential drugs against the S protein of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) has provided small molecular compounds with a high binding affinity. Unfortunately, most of these drugs do not attach with the binding interface of the receptor-binding domain (RBD)-angiotensin-converting enzyme-2 (ACE-2) complex in host cells. Molecular modeling was carried out to evaluate the potential antiviral properties of the components of the medicinal herb Uncaria tomentosa (cat's claw) focusing on the binding interface of the RBD-ACE-2 and the viral spike protein. The in silico approach starts with protein-ligand docking of 26 Cat's claw key components followed by molecular dynamics simulations and re-docked calculations. Finally, we carried out drug-likeness calculations for the most qualified cat's claw components. The structural bioinformatics approaches led to the identification of several bioactive compounds of U. tomentosa with potential therapeutic effect by dual strong interaction with interface of the RBD-ACE-2 and the ACE-2 binding site on SARS-CoV-2 RBD viral spike. In addition, in silico drug-likeness indices for these components were calculated and showed good predicted therapeutic profiles of these phytochemicals found in U. tomentosa (cat's claw). Our findings suggest the potential effectiveness of cat's claw as complementary and/or alternative medicine for COVID-19 treatment.Communicated by Ramaswamy H. Sarma.

Keywords: ACE-2; COVID-19; SARS-CoV-2; Uncaria tomentosa; cat’s claw; molecular modeling; viral spike protein.

Figure 1.

2D structures for the major bioactive constituents of the U. tomentosa studied as ligands against SARS-CoV-2/ACE-2 association and SARS-CoV-2 spike protein.

Figure 2.

Superposition of the best conformation of the most active components against ACE-2–RBD binding interface Uncarine F (in blue), Cadambine (in red), 3-isodihydrocadambine (in orange), Proanthocyanidin B2 (in light blue), Proanthocyanidin B4 (in purple blue), Proanthocyanidin C1 (in hot pink), Epiafzelechin-4β-8 (in olive), QAG-1 (in yellow), QAG-2 (in gray), QAG-4 (in violet), QAG-5 (in black), QAG-6 (in salmon) and HepOS (in bluemarine) as positive reference.

Figure 3.

A,B: The best conformation of the Proanthocyanidin C1 (A) and QAG-2 (B) within ACE-2–RBD interface (PDB: 6M17). 2D interaction mode plots between the selected compounds to the ACE-2–RBD complex. Interactions between each component and amino acids residues into ACE-2–RBD binding domain are indicated by the dashed lines. D and F into circles indicated ACE-2 and Spike proteins, respectively.

Figure 4.

A–C: The best conformation of the 3-isodihydrocadambine (A), Uncarine F (B) and Uncaric acid (C) within ACE-2–RBD interface (PDB: 6M17). 2D interaction mode plots between the selected compounds to the ACE-2–RBD complex. Interactions between each component and amino acids residues into ACE-2–RBD binding domain are indicated by the dashed lines. The code letter ‘D’ and ‘F’ indicated ACE-2 and spike proteins, respectively.

Figure 5.

A: SARS-CoV-2 spike protein protomer structure. Protomer domains RBD (in cyan), NTD (in violet), HR1 (in yellow), CD (in blue) and FP (in green). B: Connolly surface of the SARS-CoV-2 spike protein showing RBD domain. The binding site appears in cyan.

Figure 6.

Superposition of the best conformation of the all constituents of U. tomentosa and positive references alongside the SARS-CoV-2 RBD binding domain (PDB: 6VYB). Critical aminoacids are represented in cyan and positive reference (HepOS) in blue marine.

Figure 7.

2D interaction mode plots between the most active ligands inside ACE-2 active site of RBD. Interactions between each component and residues of SARS-CoV-2 RBD are indicated by the dashed lines.

Figure 8.

Backbone RMSD values of (A) 3-dihydrocadambine within SARS-CoV-2 RBD active site (red) and protein without ligand (blue). B: Proanthocyanidin B2 within SARS-CoV-2 RBD binding site (red) and protein without ligand (blue). C: Proanthocyanidin C1 at RBD/ACE-2 interface and RBD/ACE-2 complex without ligand (blue). D: QAG-2 into RBD/ACE-2 interface (red) and RBD/ACE-2 complex without ligand (blue).

Figure 9.

Radius of gyration (R_g) graphs: (A) for 3-dihydrocadambine into the binding cavity (red) and SARS-CoV-2 spike protein without ligand (blue). B: For Proanthocyanidin B2 onto active site (red) and SARS-CoV-2 spike protein without ligand (blue). C: For Proanthocyanidin C1 within binding cleft and RBD/ACE-2 complex without ligand (blue and violet). D: for QAG-2 into the binding site (red) and RBD/ACE-2 complex without ligand (blue and violet).