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. 2021 Mar 20;20(2):567-581.
doi: 10.5114/aoms/133706. eCollection 2024.

Identification of natural compounds (proanthocyanidin and rhapontin) as high-affinity inhibitors of SARS-CoV-2 Mpro and PLpro using computational strategies

Mohamed F AlAjmi  1 , Asim Azhar  2 , Sadaf Hasan  3 , Abdullah Zaid Alshabr  4 , Afzal Hussain  1 , Md Tabish Rehman  1
Affiliations

Identification of natural compounds (proanthocyanidin and rhapontin) as high-affinity inhibitors of SARS-CoV-2 Mpro and PLpro using computational strategies

Mohamed F AlAjmi et al. Arch Med Sci. .

Abstract

Introduction: The emergence of a new and highly pathogenic coronavirus (SARS-CoV-2) in Wuhan (China) and its spread worldwide has resulted in enormous social and economic losses. Amongst many proteins encoded by the SARS-CoV-2 genome, the main protease (Mpro) or chymotrypsin-like cysteine protease (3CLpro) and papain-like protease (PLpro) serve as attractive drug targets.

Material and methods: We screened a library of 2267 natural compounds against Mpro and PLpro using high throughput virtual screening (HTVS). Fifty top-scoring compounds against each protein in HTVS were further evaluated by standard-precision (SP) docking. Compounds with SP docking energy of ≤ -8.0 kcal/mol against Mpro and ≤ -5.0 kcal/mol against PLpro were subjected to extra-precision (XP) docking. Finally, six compounds against each target proteins were identified and subjected to Prime/MM-GBSA free energy calculations. Compounds with the lowest Prime/MM-GBSA energy were subjected to molecular dynamics simulation to evaluate the stability of protein-ligand complexes.

Results: Proanthocyanidin and rhapontin were identified as the most potent inhibitors of Mpro and PLpro, respectively. Analysis of protein-inhibitor interaction revealed that both protein-inhibitor complexes were stabilized by hydrogen bonding and hydrophobic interactions. Proanthocyanidin interacted with the catalytic residues (His41 and Cys145) of Mpro, while rhapontin contacted the active site residues (Trp106, His272, Asp286) of PLpro. The docking energies of proanthocyanidin and rhapontin towards their respective targets were -10.566 and -10.022 kcal/mol.

Conclusions: This study's outcome may support application of proanthocyanidin and rhapontin as a scaffold to build more potent inhibitors with desirable drug-like properties. However, it requires further validation by in vitro and in vivo studies.

Keywords: 3CLpro; COVID-19; Mpro; PLpro; molecular docking and simulation; natural compounds.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Receiver operating characteristic (ROC) curves of Mpro (A), and PLpro (B). The area under the curve (AUC) represents sensitivity and specificity of the adopted docking procedure
Figure 2
Figure 2
Extra-precision (XP) molecular docking analysis. A – Binding of proanthocyanidin to the substrate binding site of Mpro, B – molecular interaction between Mpro and proanthocyanidin, C – binding of rhapontin to the active site of PLpro, D – molecular interaction between PLpro and rhapontin
Figure 3
Figure 3
Molecular dynamics (MD) simulation analysis. A – Root mean square deviation (RMSD) of Mpro alone and in the presence of proanthocyanidin, B – RMSD of PLpro alone and in the presence of rhapontin, C – variation in root mean square fluctuation (RMSF) of Mpro in the presence of proanthocyanidin and comparison with the experimentally determined B-factor during X-ray crystallography, D – RMSF of PLpro in the presence of rhapontin and comparison with the experimentally determined B-factor during X-ray crystallography. In plots C and D, the vertical green lines shows the position of amino acid residue involved in the interaction with inhibitor. Also, light brown and teal colors indicate α-helical and β-sheet regions
Figure 4
Figure 4
Interaction pattern between proteins and their respective inhibitor as a function of simulation. A – Involvement of Mpro amino acid residues in forming different types of interaction with proanthocyanidin. B – Upper panel: The total number of contacts between Mpro and proanthocyanidin during simulation. Lower panel: the extent of amino acid residues forming contact with the inhibitor. C – Involvement of PLpro amino acid residues in forming different types of interaction with rhapontin. D – Upper panel: The total number of contacts between PLpro and rhapontin during simulation. Lower panel: the extent of amino acid residues forming contact with the inhibitor
Figure 5
Figure 5
Dependence of secondary structure element (SSE) of during simulation. Mpro-proanthocyanidin complex (A), and PLpro-rhapontin complex during simulation (B). Upper panel: Variation in SSE of proteins as a result of their respective inhibitor binding. Lower panel: Contribution of each amino acid residue in the formation of SSEs wherein α-helices are shown in light brown color and β-sheets are represented in teal color
Figure 6
Figure 6
Dependence of radius of gyration (rGyr) (A) and solvent accessible surface area (SASA) (B) of Mpro-proanthocyanidin and PLpro-rhapontin complexes as a function of simulation time
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