Effective natural inhibitors targeting granzyme B in rheumatoid arthritis by computational study
BackgroundRheumatoid arthritis (RA) is an autoimmune disease characterized by erosive arthritis, and current treatments for RA fall short of the outcomes expected by clinicians and patients.ObjectivesThis study aimed to identify novel therapeutic and prognostic targets in RA at the genomic level and...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmed.2022.1052792/full |
| _version_ | 1811198233533218816 |
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| author | Xinyu Wang Ye Jiang Pengcheng Zhou Liangxin Lin Yilin Yang Qifan Yang Jiting Zhang Dong Zhu |
| author_facet | Xinyu Wang Ye Jiang Pengcheng Zhou Liangxin Lin Yilin Yang Qifan Yang Jiting Zhang Dong Zhu |
| author_sort | Xinyu Wang |
| collection | DOAJ |
| description | BackgroundRheumatoid arthritis (RA) is an autoimmune disease characterized by erosive arthritis, and current treatments for RA fall short of the outcomes expected by clinicians and patients.ObjectivesThis study aimed to identify novel therapeutic and prognostic targets in RA at the genomic level and to screen desirable compounds with potential inhibitory effects on GZMB.MethodsWe performed differential gene analysis on GSE55235 and GSE55457 from Gene Expression Omnibus (GEO) and then obtained the intersection of the two differentially expressed genes (DEGs) lists by drawing Venn diagrams. Then we performed protein-protein interaction (PPI) network analysis, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis on the DEGs of the intersection. Next, we downloaded the crystal structure of Granzyme B (GZMB). Molecular docking technology was used to screen potential inhibitors of GZMB in subsequent experiments, and we then analyzed the toxicity and water solubility of these potential inhibitors for future drug experiments. Finally, whether the docking of these small molecules with GZMB is stable is tested by molecular dynamics.ResultsA total of 352 mutual DEGs were identified. Twenty hub genes were obtained according to PPI network analysis, among which the GZMB gene attracted the attention of our research. Three potent natural compounds, ZINC000004557101, ZINC000012495776, and ZINC000038143593, bound to GZMB, show better binding affinity. Furthermore, they are predicted to own low Ames mutagenicity, developmental toxicity potential, rodent carcinogenicity, and high tolerance to cytochrome P4502D6. Molecular dynamics simulations show that ZINC000004557101 and GZMB have more advantageous potential energy and can exist stably in a natural environment. Moreover, we finally verified the inhibitory effect of ZINC000004557101 on granzyme B by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Western blotting experiment.ConclusionRA patients showed increased GZMB expression. ZINC000004557101 is a potential drug targeting GZMB for treating RA. |
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| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2296-858X |
| language | English |
| last_indexed | 2024-04-12T01:27:22Z |
| publishDate | 2022-12-01 |
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| series | Frontiers in Medicine |
| spelling | doaj.art-7bb4137685064d62a02bbebc443d846f2022-12-22T03:53:35ZengFrontiers Media S.A.Frontiers in Medicine2296-858X2022-12-01910.3389/fmed.2022.10527921052792Effective natural inhibitors targeting granzyme B in rheumatoid arthritis by computational studyXinyu WangYe JiangPengcheng ZhouLiangxin LinYilin YangQifan YangJiting ZhangDong ZhuBackgroundRheumatoid arthritis (RA) is an autoimmune disease characterized by erosive arthritis, and current treatments for RA fall short of the outcomes expected by clinicians and patients.ObjectivesThis study aimed to identify novel therapeutic and prognostic targets in RA at the genomic level and to screen desirable compounds with potential inhibitory effects on GZMB.MethodsWe performed differential gene analysis on GSE55235 and GSE55457 from Gene Expression Omnibus (GEO) and then obtained the intersection of the two differentially expressed genes (DEGs) lists by drawing Venn diagrams. Then we performed protein-protein interaction (PPI) network analysis, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis on the DEGs of the intersection. Next, we downloaded the crystal structure of Granzyme B (GZMB). Molecular docking technology was used to screen potential inhibitors of GZMB in subsequent experiments, and we then analyzed the toxicity and water solubility of these potential inhibitors for future drug experiments. Finally, whether the docking of these small molecules with GZMB is stable is tested by molecular dynamics.ResultsA total of 352 mutual DEGs were identified. Twenty hub genes were obtained according to PPI network analysis, among which the GZMB gene attracted the attention of our research. Three potent natural compounds, ZINC000004557101, ZINC000012495776, and ZINC000038143593, bound to GZMB, show better binding affinity. Furthermore, they are predicted to own low Ames mutagenicity, developmental toxicity potential, rodent carcinogenicity, and high tolerance to cytochrome P4502D6. Molecular dynamics simulations show that ZINC000004557101 and GZMB have more advantageous potential energy and can exist stably in a natural environment. Moreover, we finally verified the inhibitory effect of ZINC000004557101 on granzyme B by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Western blotting experiment.ConclusionRA patients showed increased GZMB expression. ZINC000004557101 is a potential drug targeting GZMB for treating RA.https://www.frontiersin.org/articles/10.3389/fmed.2022.1052792/fullGZMBRAvirtual screeningdrug candidatecomputer-aided technology |
| spellingShingle | Xinyu Wang Ye Jiang Pengcheng Zhou Liangxin Lin Yilin Yang Qifan Yang Jiting Zhang Dong Zhu Effective natural inhibitors targeting granzyme B in rheumatoid arthritis by computational study Frontiers in Medicine GZMB RA virtual screening drug candidate computer-aided technology |
| title | Effective natural inhibitors targeting granzyme B in rheumatoid arthritis by computational study |
| title_full | Effective natural inhibitors targeting granzyme B in rheumatoid arthritis by computational study |
| title_fullStr | Effective natural inhibitors targeting granzyme B in rheumatoid arthritis by computational study |
| title_full_unstemmed | Effective natural inhibitors targeting granzyme B in rheumatoid arthritis by computational study |
| title_short | Effective natural inhibitors targeting granzyme B in rheumatoid arthritis by computational study |
| title_sort | effective natural inhibitors targeting granzyme b in rheumatoid arthritis by computational study |
| topic | GZMB RA virtual screening drug candidate computer-aided technology |
| url | https://www.frontiersin.org/articles/10.3389/fmed.2022.1052792/full |
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