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

Cao, Jun-Feng; Xiong, Lilin; Wu, Mei‐Hwan; Chen, Shengyan; Xu, Hengxiang; Gong, Yunli; Zhang, Lixin; Zhang, Qilan; Zhang, Xiao

doi:10.3389/fphys.2022.990469

Cited by 13 publications

(7 citation statements)

References 60 publications

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“…The interactions between ligand and receptor include both covalent and non-bonded interactions, but only non-bonded interactions (van der Waals interactions, electrostatic interactions and hydrogen bonding interactions) are generally present in complex systems of drug small molecules (ligands) and proteins (receptors) ( Dasmahapatra et al., 2022 ). Therefore, AMBER 18 was used to calculate the binding free energy by MM/GBSA method in this study ( Weng et al., 2019 ; Cao et al., 2022d ).…”

Section: Methodsmentioning

confidence: 99%

Molecular docking and molecular dynamics study Lianhua Qingwen granules (LHQW) treats COVID-19 by inhibiting inflammatory response and regulating cell survival

Cao

Gong

et al. 2022

Front. Cell. Infect. Microbiol.

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Purpose2019 Coronavirus disease (COVID-19) is endangering health of populations worldwide. Latest research has proved that Lianhua Qingwen granules (LHQW) can reduce tissue damage caused by inflammatory reactions and relieve patients’ clinical symptoms. However, the mechanism of LHQW treats COVID-19 is currently lacking. Therefore, we employed computer simulations to investigate the mechanism of LHQW treats COVID-19 by modulating inflammatory response.MethodsWe employed bioinformatics to screen active ingredients in LHQW and intersection gene targets. PPI, GO and KEGG was used to analyze relationship of intersection gene targets. Molecular dynamics simulations validated the binding stability of active ingredients and target proteins. Binding free energy, radius of gyration and the solvent accessible surface area were analyzed by supercomputer platform.ResultsCOVID-19 had 4628 gene targets, LHQW had 1409 gene targets, intersection gene targets were 415. Bioinformatics analysis showed that intersection targets were closely related to inflammation and immunomodulatory. Molecular docking suggested that active ingredients (including: licopyranocoumarin, Glycyrol and 3-3-Oxopropanoic acid) in LHQW played a role in treating COVID-19 by acting on CSF2, CXCL8, CCR5, NLRP3, IFNG and TNF. Molecular dynamics was used to prove the binding stability of active ingredients and protein targets.ConclusionThe mechanism of active ingredients in LHQW treats COVID-19 was investigated by computer simulations. We found that active ingredients in LHQW not only reduce cell damage and tissue destruction by inhibiting the inflammatory response through CSF2, CXCL8, CCR5 and IFNG, but also regulate cell survival and growth through NLRP3 and TNF thereby reducing apoptosis.

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Section: Methodsmentioning

confidence: 99%

Molecular docking and molecular dynamics study Lianhua Qingwen granules (LHQW) treats COVID-19 by inhibiting inflammatory response and regulating cell survival

Cao

Gong

et al. 2022

Front. Cell. Infect. Microbiol.

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“…Finally, the consistency of the binding mode can indicate the correctness of the molecular docking scheme. And the value of molecular docking score was greater than 6.5 among the target proteins and the small molecule N-0385, it was considered to be tightly bound ( Cao J. et al, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

“…Gene targets screening was performed at p < 0.05 to analyze the main signaling pathways and biological processes of COVID-19. Omicshare tool platform was used to visualize the results of GO enrichment and KEGG enrichment (Cao et al, 2022b).…”

Section: Gene Target Enrichment Analysismentioning

confidence: 99%

Mechanism of N-0385 blocking SARS-CoV-2 to treat COVID-19 based on molecular docking and molecular dynamics

Cao

Xiong²,

Wu³

et al. 2022

Front. Microbiol.

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Purpose2019 Coronavirus disease (COVID-19) has caused millions of confirmed cases and deaths worldwide. TMPRSS2-mediated hydrolysis and maturation of spike protein is essential for SARS-CoV-2 infection in vivo. The latest research found that a TMPRSS2 inhibitor called N-0385 could effectively prevent the infection of the SARS-CoV-2 and its variants. However, it is not clear about the mechanism of N-0385 treatment COVID-19. Therefore, this study used computer simulations to investigate the mechanism of N-0385 treatment COVID-19 by impeding SARS-CoV-2 infection.MethodsThe GeneCards database was used to search disease gene targets, core targets were analyzed by PPI, GO and KEGG. Molecular docking and molecular dynamics were used to validate and analyze the binding stability of small molecule N-0385 to target proteins. The supercomputer platform was used to simulate and analyze the number of hydrogen bonds, binding free energy, stability of protein targets at the residue level, radius of gyration and solvent accessible surface area.ResultsThere were 4,600 COVID-19 gene targets from GeneCards database. PPI, GO and KEGG analysis indicated that signaling pathways of immune response and inflammation played crucial roles in COVID-19. Molecular docking showed that N-0385 could block SARS-CoV-2 infection and treat COVID-19 by acting on ACE2, TMPRSS2 and NLRP3. Molecular dynamics was used to demonstrate that the small molecule N-0385 could form very stable bindings with TMPRSS2 and TLR7.ConclusionThe mechanism of N-0385 treatment COVID-19 was investigated by molecular docking and molecular dynamics simulation. We speculated that N-0385 may not only inhibit SARS-CoV-2 invasion directly by acting on TMPRSS2, ACE2 and DPP4, but also inhibit the immune recognition process and inflammatory response by regulating TLR7, NLRP3 and IL-10 to prevent SARS-CoV-2 invasion. Therefore, these results suggested that N-0385 may act through multiple targets to reduce SARS-CoV-2 infection and damage caused by inflammatory responses.

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“…On the other hand, it was revealed that CBED may exhibited a dual inhibitory effect on XOD activity and NLRP3 inflammasome activation in a dose dependent manner ( 103 ). On the basis of bioinformatics analysis and molecular docking, it was found that dapansutrile may not only selectively target NLRP3 to attenuate the inflammatory response and pyroptosis, but also block the chemotaxis and activation of inflammatory cells by regulating IL-1β, IL6, IL17A, IL18, MMP3, CXCL8, and TNF-α ( 104 ). Overall, dapansutrile, also known as OLT1177, suppressed MSU-induced joint swelling and inflammation, and may be highly effective in ameliorating GA by functioning on NLRP3 inflammasome ( 105 ).…”

Section: Therapeutic Strategies For Targeting Nlrp3 In Gamentioning

confidence: 99%

Role of NLRP3 in the pathogenesis and treatment of gout arthritis

Liu

Wang

2023

Front. Immunol.

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Gout arthritis (GA) is a common and curable type of inflammatory arthritis that has been attributed to a combination of genetic, environmental and metabolic factors. Chronic deposition of monosodium urate (MSU) crystals in articular and periarticular spaces as well as subsequent activation of innate immune system in the condition of persistent hyperuricemia are the core mechanisms of GA. As is well known, drugs for GA therapy primarily consists of rapidly acting anti-inflammatory agents and life-long uric acid lowering agents, and their therapeutic outcomes are far from satisfactory. Although MSU crystals in articular cartilage detected by arthrosonography or in synovial fluid found by polarization microscopy are conclusive proofs for GA, the exact molecular mechanism of NLRP3 inflammasome activation in the course of GA still remains mysterious, severely restricting the early diagnosis and therapy of GA. On the one hand, the activation of Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome requires nuclear factor kappa B (NF-κB)-dependent transcriptional enhancement of NLRP3, precursor (pro)-caspase-1 and pro-IL-1β, as well as the assembly of NLRP3 inflammasome complex and sustained release of inflammatory mediators and cytokines such as IL-1β, IL-18 and caspase-1. On the other hand, NLRP3 inflammasome activated by MSU crystals is particularly relevant to the initiation and progression of GA, and thus may represent a prospective diagnostic biomarker and therapeutic target. As a result, pharmacological inhibition of the assembly and activation of NLRP3 inflammasome may also be a promising avenue for GA therapy. Herein, we first introduced the functional role of NLRP3 inflammasome activation and relevant biological mechanisms in GA based on currently available evidence. Then, we systematically reviewed therapeutic strategies for targeting NLRP3 by potentially effective agents such as natural products, novel compounds and noncoding RNAs (ncRNAs) in the treatment of MSU-induced GA mouse models. In conclusion, our present review may have significant implications for the pathogenesis, diagnosis and therapy of GA.

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

Cited by 13 publications

References 60 publications

Molecular docking and molecular dynamics study Lianhua Qingwen granules (LHQW) treats COVID-19 by inhibiting inflammatory response and regulating cell survival

Molecular docking and molecular dynamics study Lianhua Qingwen granules (LHQW) treats COVID-19 by inhibiting inflammatory response and regulating cell survival

Mechanism of N-0385 blocking SARS-CoV-2 to treat COVID-19 based on molecular docking and molecular dynamics

Role of NLRP3 in the pathogenesis and treatment of gout arthritis

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