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. 2022 Aug 29:13:990469.
doi: 10.3389/fphys.2022.990469. eCollection 2022.

Exploring the mechanism of action of dapansutrile in the treatment of gouty arthritis based on molecular docking and molecular dynamics

Jun-Feng Cao  1 , Xingyu Yang  1 , Li Xiong  1 , Mei Wu  1 , Shengyan Chen  1 , Hengxiang Xu  1 , Yunli Gong  2 , Lixin Zhang  3 , Qilan Zhang  4 , Xiao Zhang  4
Affiliations

Exploring the mechanism of action of dapansutrile in the treatment of gouty arthritis based on molecular docking and molecular dynamics

Jun-Feng Cao et al. Front Physiol. .

Abstract

Purpose: Dapansutrile is an orally active β-sulfonyl nitrile compound that selectively inhibits the NLRP3 inflammasome. Clinical studies have shown that dapansutrile is active in vivo and limits the severity of endotoxin-induced inflammation and joint arthritis. However, there is currently a lack of more in-depth research on the effect of dapansutrile on protein targets such as NLRP3 in gouty arthritis. Therefore, we used molecular docking and molecular dynamics to explore the mechanism of dapansutrile on NLRP3 and other related protein targets. Methods: We use bioinformatics to screen active pharmaceutical ingredients and potential disease targets. The disease-core gene target-drug network was established and molecular docking was used for verification. Molecular dynamics simulations were utilized to verify and analyze the binding stability of small molecule drugs to target proteins. The supercomputer platform was used to measure and analyze the binding free energy, the number of hydrogen bonds, the stability of the protein target at the residue level, the radius of gyration and the solvent accessible surface area. Results: The protein interaction network screened out the core protein targets (such as: NLRP3, TNF, IL1B) of gouty arthritis. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that gouty arthritis mainly played a vital role by the signaling pathways of inflammation and immune response. Molecular docking showed that dapansutrile play a role in treating gouty arthritis by acting on the related protein targets such as NLRP3, IL1B, IL6, etc. Molecular dynamics was used to prove and analyze the binding stability of active ingredients and protein targets, the simulation results found that dapansutrile forms a very stable complex with IL1B. Conclusion: We used bioinformatics analysis and computer simulation system to comprehensively explore the mechanism of dapansutrile acting on NLRP3 and other protein targets in gouty arthritis. This study found that dapansutrile may not only directly inhibit NLRP3 to reduce the inflammatory response and pyroptosis, but also hinder the chemotaxis and activation of inflammatory cells by regulating IL1B, IL6, IL17A, IL18, MMP3, CXCL8, and TNF. Therefore, dapansutrile treats gouty arthritis by attenuating inflammatory response, inflammatory cell chemotaxis and extracellular matrix degradation by acting on multiple targets.

Keywords: NLRP3; dapansutrile; gouty arthritis; molecular docking; molecular dynamics.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Protein-protein interaction (PPI) network. (A) PPI network of protein target, (B) PPI network of core protein target (confidence > 0.95).
FIGURE 2
FIGURE 2
Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Analysis of related genes. (A) The top 5 terms in biological processes (BP) were greatly enriched. (B) The subnetwork displayed the top 5 BP terms and related genes. (C) The top 5 terms in cellular components (CC) were greatly enriched. (D) The subnetwork displayed the top 5 CC terms and related genes. (E) The top 5 terms in molecular function (MF) were greatly enriched. (F) The subnetwork displayed the top 5 MF terms and related genes. (G) The top 15 KEGG pathways were showed. (H) The subnetworks displayed the top 15 KEGG pathways.
FIGURE 3
FIGURE 3
Disease-core gene target-drug network. Square nodes represent gene targets, triangular nodes represent signaling pathways (KEGG), and octagonal nodes represent gene ontology (GO) of related genes.
FIGURE 4
FIGURE 4
Molecular docking of active ingredients and core targets. (A) Dapansutrile/CXCL8, (B) Dapansutrile/IL1B, (C) Dapansutrile/IL6, (D) Dapansutrile/IL17A, (E) Dapansutrile/IL18, (F) Dapansutrile/MMP3, (G) Dapansutrile/NLRP3, (H) Dapansutrile/TNF.
FIGURE 5
FIGURE 5
Complex root mean square deviation (RMSD) difference over time.
FIGURE 6
FIGURE 6
Changes in the number of hydrogen bonds between small molecule ligands and protein receptors in complex system simulations (A) Dapansutrile/CXCL8, (B) Dapansutrile/IL1B, (C) Dapansutrile/IL6, (D) Dapansutrile/IL17A, (E) Dapansutrile/IL18, (F) Dapansutrile/MMP3, (G) Dapansutrile/NLRP3, (H) Dapansutrile/TNF.
FIGURE 7
FIGURE 7
Changes in the stability of protein targets at the residue level (A) Dapansutrile/CXCL8, (B) Dapansutrile/IL1B, (C) Dapansutrile/IL6, (D) Dapansutrile/IL17A, (E) Dapansutrile/IL18, (F) Dapansutrile/MMP3, (G) Dapansutrile/NLRP3, (H) Dapansutrile/TNF.
FIGURE 8
FIGURE 8
Analysis of protein folding state and overall conformation.
FIGURE 9
FIGURE 9
Analysis of solvent accessible surface area (SASA).
See this image and copyright information in PMC

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