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. 2023 Feb 2;28(3):1444.
doi: 10.3390/molecules28031444.

Potential Inhibitors of Monkeypox Virus Revealed by Molecular Modeling Approach to Viral DNA Topoisomerase I

Affiliations

Potential Inhibitors of Monkeypox Virus Revealed by Molecular Modeling Approach to Viral DNA Topoisomerase I

Xiaopeng Hu et al. Molecules. .

Abstract

The monkeypox outbreak has become a global public health emergency. The lack of valid and safe medicine is a crucial obstacle hindering the extermination of orthopoxvirus infections. The identification of potential inhibitors from natural products, including Traditional Chinese Medicine (TCM), by molecular modeling could expand the arsenal of antiviral chemotherapeutic agents. Monkeypox DNA topoisomerase I (TOP1) is a highly conserved viral DNA repair enzyme with a small size and low homology to human proteins. The protein model of viral DNA TOP1 was obtained by homology modeling. The reliability of the TOP1 model was validated by analyzing its Ramachandran plot and by determining the compatibility of the 3D model with its sequence using the Verify 3D and PROCHECK services. In order to identify potential inhibitors of TOP1, an integrated library of 4103 natural products was screened via Glide docking. Surface Plasmon Resonance (SPR) was further implemented to assay the complex binding affinity. Molecular dynamics simulations (100 ns) were combined with molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) computations to reveal the binding mechanisms of the complex. As a result, three natural compounds were highlighted as potential inhibitors via docking-based virtual screening. Rosmarinic acid, myricitrin, quercitrin, and ofloxacin can bind TOP1 with KD values of 2.16 μM, 3.54 μM, 4.77 μM, and 5.46 μM, respectively, indicating a good inhibitory effect against MPXV. The MM/PBSA calculations revealed that rosmarinic acid had the lowest binding free energy at -16.18 kcal/mol. Myricitrin had a binding free energy of -13.87 kcal/mol, quercitrin had a binding free energy of -9.40 kcal/mol, and ofloxacin had a binding free energy of -9.64 kcal/mol. The outputs (RMSD/RMSF/Rg/SASA) also indicated that the systems were well-behaved towards the complex. The selected compounds formed several key hydrogen bonds with TOP1 residues (TYR274, LYS167, GLY132, LYS133, etc.) via the binding mode analysis. TYR274 was predicted to be a pivotal residue for compound interactions in the binding pocket of TOP1. The results of the enrichment analyses illustrated the potential pharmacological networks of rosmarinic acid. The molecular modeling approach may be acceptable for the identification and design of novel poxvirus inhibitors; however, further studies are warranted to evaluate their therapeutic potential.

Keywords: DNA topoisomerase I (TOP1); Surface Plasmon Resonance (SPR); enrichment analyses; molecular dynamics simulation; monkeypox virus; natural products; rosmarinic acid.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(a) Cartoon views of predicted 3D structures of the TOP1 from the SWISS-MODEL; (b) the structural alignment between the modeled TOP1 and template TOP1 (PDB ID 3IGC) from the variola virus (green—modeled TOP1; cyan—template TOP1).
Figure 2
Figure 2
(a) Ramachandran plot towards TOP1 model; (b) results of the Verify_3D analysis of the TOP1 model.
Figure 3
Figure 3
Cartoon on behalf of TOP1 targeted with: (A,B) rosmarinic acid; (C,D) myricitrin; (E,F) quercitrin; (G,H) ofloxacin. The 3D combining site was revealed as a cartoon representation, as well as the compounds, shown as sticks. The 2D one was further visualized and signed in the indicated atoms with the interaction force, including the hydrogen bond and hydrophobic contact.
Figure 3
Figure 3
Cartoon on behalf of TOP1 targeted with: (A,B) rosmarinic acid; (C,D) myricitrin; (E,F) quercitrin; (G,H) ofloxacin. The 3D combining site was revealed as a cartoon representation, as well as the compounds, shown as sticks. The 2D one was further visualized and signed in the indicated atoms with the interaction force, including the hydrogen bond and hydrophobic contact.
Figure 4
Figure 4
Root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and solvent-accessible surface area (SASA) graphs of the TOP1–ligand complexes produced over a 100 ns molecular dynamics simulation. (A) RMSD versus time plot of TOP1–ligand complexes; (B) analysis of the RMSF trajectories of residues of TOP1–ligand complexes; (C) Rg versus time plot of TOP1–ligand complexes; (D) SASA versus time plot of TOP1–ligand complexes; as for the unbound protein, TOP1, TOP1+Ofloxacin, TOP1+Rosmarinic acid, TOP1+Myricitrin, and TOP1+Quercitrin are represented as red, black, purple, blue, and green, respectively.
Figure 5
Figure 5
Decomposition of MM/PBSA into contributions from individual residues for (A) TOP1+Rosmarinic acid; (B) TOP1+Myricitrin; (C) TOP1+Quercitrin; (D) TOP1+Ofloxacin.
Figure 6
Figure 6
The direct binding affinity of selected compounds with vaccinia virus TOP1 was identified by SPR. (A) TOP1+Rosmarinic acid; (B) TOP1+Myricitrin; (C) TOP1+Quercitrin; (D) TOP1+Ofloxacin.
Figure 7
Figure 7
Analysis of the feasible targets toward rosmarinic acid through GO and KEGG enrichment. (A) The forecasted targets mostly take part in carbonate dehydratase activity in terms of the molecular function; as for the cellular component, the predicted targets mainly existed in cytosol; one-carbon metabolic is considered the primary progress during the biological process. (B) The circle diameter represents the number of rosmarinic acid-related genes. The deeper shield of orange shows the greater disparity. Forecasted genes towards rosmarinic acid (CA12, CA1, CA5B, CA2, CA4, CA7, CA6, CA9, CA14, and CA13) were allocated to the signaling pathway of nitrogen metabolism, with notable differences.
Figure 7
Figure 7
Analysis of the feasible targets toward rosmarinic acid through GO and KEGG enrichment. (A) The forecasted targets mostly take part in carbonate dehydratase activity in terms of the molecular function; as for the cellular component, the predicted targets mainly existed in cytosol; one-carbon metabolic is considered the primary progress during the biological process. (B) The circle diameter represents the number of rosmarinic acid-related genes. The deeper shield of orange shows the greater disparity. Forecasted genes towards rosmarinic acid (CA12, CA1, CA5B, CA2, CA4, CA7, CA6, CA9, CA14, and CA13) were allocated to the signaling pathway of nitrogen metabolism, with notable differences.

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