Exploring the mechanism of action of dapansutrile in the treatment of gouty arthritis based on molecular docking and molecular dynamics
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...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-08-01
|
| Series: | Frontiers in Physiology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2022.990469/full |
| _version_ | 1817996112112386048 |
|---|---|
| author | Jun-Feng Cao Xingyu Yang Li Xiong Mei Wu Shengyan Chen Hengxiang Xu Yunli Gong Lixin Zhang Qilan Zhang Xiao Zhang |
| author_facet | Jun-Feng Cao Xingyu Yang Li Xiong Mei Wu Shengyan Chen Hengxiang Xu Yunli Gong Lixin Zhang Qilan Zhang Xiao Zhang |
| author_sort | Jun-Feng Cao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T02:17:18Z |
| format | Article |
| id | doaj.art-2ec011995a6f434da36c925cb8ca0b2c |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-04-14T02:17:18Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-2ec011995a6f434da36c925cb8ca0b2c2022-12-22T02:18:08ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2022-08-011310.3389/fphys.2022.990469990469Exploring the mechanism of action of dapansutrile in the treatment of gouty arthritis based on molecular docking and molecular dynamicsJun-Feng Cao0 Xingyu Yang1 Li Xiong2Mei Wu3Shengyan Chen4Hengxiang Xu5Yunli Gong6Lixin Zhang7Qilan Zhang8Xiao Zhang9Clinical Medicine, Chengdu Medical College, Chengdu, ChinaClinical Medicine, Chengdu Medical College, Chengdu, ChinaClinical Medicine, Chengdu Medical College, Chengdu, ChinaClinical Medicine, Chengdu Medical College, Chengdu, ChinaClinical Medicine, Chengdu Medical College, Chengdu, ChinaClinical Medicine, Chengdu Medical College, Chengdu, ChinaLaboratory Medicine, Chengdu Medical College, Chengdu, ChinaYunnan Academy of Forestry Sciences, Kunming, Yunnan, ChinaChengdu Medical College of Basic Medical Sciences, Chengdu, ChinaChengdu Medical College of Basic Medical Sciences, Chengdu, ChinaPurpose: 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.https://www.frontiersin.org/articles/10.3389/fphys.2022.990469/fullgouty arthritisdapansutrileNLRP3molecular dockingmolecular dynamics |
| spellingShingle | Jun-Feng Cao Xingyu Yang Li Xiong Mei Wu Shengyan Chen Hengxiang Xu Yunli Gong Lixin Zhang Qilan Zhang Xiao Zhang Exploring the mechanism of action of dapansutrile in the treatment of gouty arthritis based on molecular docking and molecular dynamics Frontiers in Physiology gouty arthritis dapansutrile NLRP3 molecular docking molecular dynamics |
| title | Exploring the mechanism of action of dapansutrile in the treatment of gouty arthritis based on molecular docking and molecular dynamics |
| title_full | Exploring the mechanism of action of dapansutrile in the treatment of gouty arthritis based on molecular docking and molecular dynamics |
| title_fullStr | Exploring the mechanism of action of dapansutrile in the treatment of gouty arthritis based on molecular docking and molecular dynamics |
| title_full_unstemmed | Exploring the mechanism of action of dapansutrile in the treatment of gouty arthritis based on molecular docking and molecular dynamics |
| title_short | Exploring the mechanism of action of dapansutrile in the treatment of gouty arthritis based on molecular docking and molecular dynamics |
| title_sort | exploring the mechanism of action of dapansutrile in the treatment of gouty arthritis based on molecular docking and molecular dynamics |
| topic | gouty arthritis dapansutrile NLRP3 molecular docking molecular dynamics |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2022.990469/full |
| work_keys_str_mv | AT junfengcao exploringthemechanismofactionofdapansutrileinthetreatmentofgoutyarthritisbasedonmoleculardockingandmoleculardynamics AT xingyuyang exploringthemechanismofactionofdapansutrileinthetreatmentofgoutyarthritisbasedonmoleculardockingandmoleculardynamics AT lixiong exploringthemechanismofactionofdapansutrileinthetreatmentofgoutyarthritisbasedonmoleculardockingandmoleculardynamics AT meiwu exploringthemechanismofactionofdapansutrileinthetreatmentofgoutyarthritisbasedonmoleculardockingandmoleculardynamics AT shengyanchen exploringthemechanismofactionofdapansutrileinthetreatmentofgoutyarthritisbasedonmoleculardockingandmoleculardynamics AT hengxiangxu exploringthemechanismofactionofdapansutrileinthetreatmentofgoutyarthritisbasedonmoleculardockingandmoleculardynamics AT yunligong exploringthemechanismofactionofdapansutrileinthetreatmentofgoutyarthritisbasedonmoleculardockingandmoleculardynamics AT lixinzhang exploringthemechanismofactionofdapansutrileinthetreatmentofgoutyarthritisbasedonmoleculardockingandmoleculardynamics AT qilanzhang exploringthemechanismofactionofdapansutrileinthetreatmentofgoutyarthritisbasedonmoleculardockingandmoleculardynamics AT xiaozhang exploringthemechanismofactionofdapansutrileinthetreatmentofgoutyarthritisbasedonmoleculardockingandmoleculardynamics |