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. 2024 Feb 25;29(5):998.
doi: 10.3390/molecules29050998.

Identification of Phytochemicals from Arabian Peninsula Medicinal Plants as Strong Binders to SARS-CoV-2 Proteases (3CLPro and PLPro) by Molecular Docking and Dynamic Simulation Studies

Quaiser Saquib  1 , Ahmed H Bakheit  2 , Sarfaraz Ahmed  3 , Sabiha M Ansari  4 , Abdullah M Al-Salem  1 , Abdulaziz A Al-Khedhairy  1
Affiliations

Identification of Phytochemicals from Arabian Peninsula Medicinal Plants as Strong Binders to SARS-CoV-2 Proteases (3CLPro and PLPro) by Molecular Docking and Dynamic Simulation Studies

Quaiser Saquib et al. Molecules. .

Abstract

We provide promising computational (in silico) data on phytochemicals (compounds 1-10) from Arabian Peninsula medicinal plants as strong binders, targeting 3-chymotrypsin-like protease (3CLPro) and papain-like proteases (PLPro) of SARS-CoV-2. Compounds 1-10 followed the Lipinski rules of five (RO5) and ADMET analysis, exhibiting drug-like characters. Non-covalent (reversible) docking of compounds 1-10 demonstrated their binding with the catalytic dyad (CYS145 and HIS41) of 3CLPro and catalytic triad (CYS111, HIS272, and ASP286) of PLPro. Moreover, the implementation of the covalent (irreversible) docking protocol revealed that only compounds 7, 8, and 9 possess covalent warheads, which allowed the formation of the covalent bond with the catalytic dyad (CYS145) in 3CLPro and the catalytic triad (CYS111) in PLPro. Root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and radius of gyration (Rg) analysis from molecular dynamic (MD) simulations revealed that complexation between ligands (compounds 7, 8, and 9) and 3CLPro and PLPro was stable, and there was less deviation of ligands. Overall, the in silico data on the inherent properties of the above phytochemicals unravel the fact that they can act as reversible inhibitors for 3CLPro and PLPro. Moreover, compounds 7, 8, and 9 also showed their novel properties to inhibit dual targets by irreversible inhibition, indicating their effectiveness for possibly developing future drugs against SARS-CoV-2. Nonetheless, to confirm the theoretical findings here, the effectiveness of the above compounds as inhibitors of 3CLPro and PLPro warrants future investigations using suitable in vitro and in vivo tests.

Keywords: 3CLPro; PLPro; SARS-CoV-2; docking; medicinal plants; molecular dynamic simulations.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
AlogP98 versus 2D PSA ellipses plot. AlogP98 versus 2D PSA ellipses plotted from the calculated values of ADMET indicate the confidence levels (95% and 99%) of HIA and BBB penetration models.
Figure 2
Figure 2
Active site in SARS-CoV-2 target proteins 3CLPro and PLPro. (Aa) Ribbon structure of 3CLPro (PDB ID: 6W63) with ligand (X77) in the active site of the target protein. (Ab) Magnified view of the active site of 3CLPro showing the catalytic dyad of residues interacting with X77. (Bc) Ribbon structure of PLPro (PDB ID: 6WUU) with ligand (VIR250) in the active site of the target protein. (Bd) Magnified view of the active site of PLPro showing the catalytic triad of residues interacting with VIR250. Helices are red, beta sheets are cyan, turns are green, and coils are white. Images are generated by using MOE software (version 2015.1).
Figure 3
Figure 3
Two-dimensional view of 3CLPro showing non-covalent binding with compound 1 (A), compound 2 (B), compound 3 (C), compound 4 (D), compound 5 (E), and compound 6 (F). The surface representation and magnified view of compounds 1–6 in the active site of 3CLPro is shown in Supplementary Figures S3–S8. Images are generated by using MOE software.
Figure 4
Figure 4
Two-dimensional view of 3CLPro showing non-covalent binding with compound 7 (A), compound 8 (B), compound 9 (C), and compound 10 (D). The surface representation and magnified view of compounds 7–10 in the active site of 3CLPro is shown in Supplementary Figures S9–S12. Images were generated by using MOE software.
Figure 5
Figure 5
Two-dimensional view of PLPro showing non-covalent binding with compound 1 (A), compound 2 (B), compound 3 (C), compound 4 (D), compound 5 (E), and compound 6 (F). Surface representation and magnified view of compounds 1–6 in the active site of PLPro is shown in Supplementary Figures S13–S18. Images are generated by the use of MOE software.
Figure 6
Figure 6
Two-dimensional view of PLPro showing non-covalent binding with compound 7 (A), compound 8 (B), compound 9 (C), and compound 10 (D). The surface representation and magnified view of compounds 1–6 in the active site of PLPro is shown in Supplementary Figures S19–S22. Images are generated by using MOE software.
Figure 7
Figure 7
Compounds 7, 8, and 9 double-bond moieties and sulfur atoms of the CYS145 residue at the active site of 3CLPro exhibit covalent bond formation. Surface representation of 3CLPro docked with compound 7 (A), compound 8 (B), and compound 9 (C). The solvent-exposed region of 3CLPro is dark yellow, hydrophobic regions are yellow, and polar regions are red. Compounds 7–9 are in green. Magnified view of the 3CLPro active site occupied by compounds 7 (a), 8 (b), and 9 (c), showing their interactions with other amino acid residues in the active site. Bond colors in the magnified view of stick models are as follows: H-bond (black color), H-π bond (dark red), Van der Waals clashes (dark blue), atoms (element color), and residues are labeled as blue texts. Images are generated by using MOE software.
Figure 8
Figure 8
Compounds 7, 8, and 9 double-bond moieties and sulfur atoms of the CYS111 residue at the active site of PLPro exhibit covalent bond formation. Surface representation of PLPro docked with compound 7 (A), compound 8 (B) and compound 9 (C). The solvent-exposed region of PLPro is dark yellow, hydrophobic regions are yellow, and polar regions are red. Compounds 7–9 are in green. Magnified view of the PLPro active site occupied by compounds 7 (a), 8 (b), and 9 (c), showing their interactions with other amino acid residues in the active site. Bond colors in the magnified view of stick models are as follows: H-bond (black color), H-π bond (dark red), Van der Waals clashes (dark blue), atoms (element color), and residues are labeled as blue texts. Images are generated by using MOE software.
Figure 9
Figure 9
RMSD of unbound 3CLPro (A), PLPro (B), and during their complexation with compounds 7, 8, and 9 as a function of time. RMSF of 3CLPro (C) and PLPro (D) shows the flexibility and stability of amino acid residues in the absence and presence of ligands (compounds 7, 8, and 9). Rg of 3CLPro (E) and PLPro (F) exhibiting the compactness of amino acid residues in the absence and presence of ligands (compounds 7, 8, and 9). The data for RMSD, RMSF and Rg generated from MD simulations were replotted using GraphPad Prism 9.
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