Integrated approaches for the recognition of small molecule inhibitors for Toll-like receptor 4
Toll-like receptors (TLRs) are pattern recognition receptors present on the surface of cells playing a crucial role in innate immunity. One of the TLRs, TLR4, recognizes LPS (Lipopolysaccharide) as its ligand leading to the release of anti-inflammatory mediators as well as pro-inflammatory cytokines...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-01-01
|
| Series: | Computational and Structural Biotechnology Journal |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037023002556 |
| _version_ | 1827577643235540992 |
|---|---|
| author | Shailya Verma Purushotham Reddy R. Sowdhamini |
| author_facet | Shailya Verma Purushotham Reddy R. Sowdhamini |
| author_sort | Shailya Verma |
| collection | DOAJ |
| description | Toll-like receptors (TLRs) are pattern recognition receptors present on the surface of cells playing a crucial role in innate immunity. One of the TLRs, TLR4, recognizes LPS (Lipopolysaccharide) as its ligand leading to the release of anti-inflammatory mediators as well as pro-inflammatory cytokines through signal transduction and domain recruitment. TLR4 homodimerizes at its intracellular TIR (Toll/interleukin-1 receptor) domain that helps in the recruitment of the TRAM/TICAM2 (TIR domain-containing adaptor molecule 2) molecule. TRAM also contains TIR domain which in turn, dimerizes and functions as an adapter protein to further recruit TRIF/TICAM1 (TIR domain-containing adaptor molecule 1) protein for mediating downstream signaling. Apart from LPS, TLR4 also recognizes endogenous ligands like fibrinogen, HMGB1, and hyaluronan in autoimmune conditions and sepsis. We employed computational approaches to target TRAM and recognize small molecule inhibitors from small molecules of natural origin, as contained in the Super Natural II database. Finally, cell reporter assays and NMR studies enabled the identification of promising lead compounds. Hence, this study aims to attenuate the signaling of the TLR4-TRAM-TRIF cascade in these auto-inflammatory conditions. |
| first_indexed | 2024-03-08T21:30:44Z |
| format | Article |
| id | doaj.art-fb02d01ad0924b98a9735dba8fd0f447 |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-03-08T21:30:44Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-fb02d01ad0924b98a9735dba8fd0f4472023-12-21T07:31:49ZengElsevierComputational and Structural Biotechnology Journal2001-03702023-01-012136803689Integrated approaches for the recognition of small molecule inhibitors for Toll-like receptor 4Shailya Verma0Purushotham Reddy1R. Sowdhamini2National Centre for Biological Sciences (TIFR), GKVK campus, Bangalore 560065, IndiaNational Centre for Biological Sciences (TIFR), GKVK campus, Bangalore 560065, India; NMR-Analytical research and development, Aurobindo Pharma, Research center-II, Hyderabad, Telangana 502307, IndiaNational Centre for Biological Sciences (TIFR), GKVK campus, Bangalore 560065, India; Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India; Institute of Bioinformatics and Applied Biotechnology, Electronic City, 560100, India; Corresponding author at: National Centre for Biological Sciences (TIFR), GKVK campus, Bangalore, 560065, India.Toll-like receptors (TLRs) are pattern recognition receptors present on the surface of cells playing a crucial role in innate immunity. One of the TLRs, TLR4, recognizes LPS (Lipopolysaccharide) as its ligand leading to the release of anti-inflammatory mediators as well as pro-inflammatory cytokines through signal transduction and domain recruitment. TLR4 homodimerizes at its intracellular TIR (Toll/interleukin-1 receptor) domain that helps in the recruitment of the TRAM/TICAM2 (TIR domain-containing adaptor molecule 2) molecule. TRAM also contains TIR domain which in turn, dimerizes and functions as an adapter protein to further recruit TRIF/TICAM1 (TIR domain-containing adaptor molecule 1) protein for mediating downstream signaling. Apart from LPS, TLR4 also recognizes endogenous ligands like fibrinogen, HMGB1, and hyaluronan in autoimmune conditions and sepsis. We employed computational approaches to target TRAM and recognize small molecule inhibitors from small molecules of natural origin, as contained in the Super Natural II database. Finally, cell reporter assays and NMR studies enabled the identification of promising lead compounds. Hence, this study aims to attenuate the signaling of the TLR4-TRAM-TRIF cascade in these auto-inflammatory conditions.http://www.sciencedirect.com/science/article/pii/S2001037023002556Toll-like receptorTIR domainAutoimmuneVirtual screeningMD simulationsReporter assay |
| spellingShingle | Shailya Verma Purushotham Reddy R. Sowdhamini Integrated approaches for the recognition of small molecule inhibitors for Toll-like receptor 4 Computational and Structural Biotechnology Journal Toll-like receptor TIR domain Autoimmune Virtual screening MD simulations Reporter assay |
| title | Integrated approaches for the recognition of small molecule inhibitors for Toll-like receptor 4 |
| title_full | Integrated approaches for the recognition of small molecule inhibitors for Toll-like receptor 4 |
| title_fullStr | Integrated approaches for the recognition of small molecule inhibitors for Toll-like receptor 4 |
| title_full_unstemmed | Integrated approaches for the recognition of small molecule inhibitors for Toll-like receptor 4 |
| title_short | Integrated approaches for the recognition of small molecule inhibitors for Toll-like receptor 4 |
| title_sort | integrated approaches for the recognition of small molecule inhibitors for toll like receptor 4 |
| topic | Toll-like receptor TIR domain Autoimmune Virtual screening MD simulations Reporter assay |
| url | http://www.sciencedirect.com/science/article/pii/S2001037023002556 |
| work_keys_str_mv | AT shailyaverma integratedapproachesfortherecognitionofsmallmoleculeinhibitorsfortolllikereceptor4 AT purushothamreddy integratedapproachesfortherecognitionofsmallmoleculeinhibitorsfortolllikereceptor4 AT rsowdhamini integratedapproachesfortherecognitionofsmallmoleculeinhibitorsfortolllikereceptor4 |