Unveiling molecular insights: in silico exploration of TLR4 antagonist for management of dry eye syndrome
Background Dry eye disease is the most commonplace multifractional ocular complication, which has already affected millions of people in the world. It is identified by the excessive buildup of reactive oxygen species, leading to substantial corneal epithelial cell demise and ocular surface inflammat...
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BMJ Publishing Group
2024-05-01
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| Series: | BMJ Open Ophthalmology |
| Online Access: | https://bmjophth.bmj.com/content/9/1/e001610.full |
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| author | Kothandan Sudhakar Neeru Dugar Srikanth Jupudi Ravichandran Ashwin Kuppusamy Gowthamarajan |
| author_facet | Kothandan Sudhakar Neeru Dugar Srikanth Jupudi Ravichandran Ashwin Kuppusamy Gowthamarajan |
| author_sort | Kothandan Sudhakar |
| collection | DOAJ |
| description | Background Dry eye disease is the most commonplace multifractional ocular complication, which has already affected millions of people in the world. It is identified by the excessive buildup of reactive oxygen species, leading to substantial corneal epithelial cell demise and ocular surface inflammation attributed to TLR4. In this study, we aimed to identify potential compounds to treat of dry eye syndrome by exploring in silico methods.Methods In this research, molecular docking and dynamics simulation tests were used to examine the effects of selected compounds on TLR4 receptor. Compounds were extracted from different databases and were prepared and docked against TLR4 receptor via Autodock Vina. Celastrol, lumacaftor and nilotinib were selected for further molecular dynamics studies for a deeper understanding of molecular systems consisting of protein and ligands by using the Desmond module of the Schrodinger Suite.Results The docking results revealed that the compounds are having binding affinity in the range of −5.1 to −8.78 based on the binding affinity and three-dimensional interactions celastrol, lumacaftor and nilotinib were further studied for their activity by molecular dynamics. Among the three compounds, celastrol was the most stable based on molecular dynamics trajectory analysis from 100 ns in the catalytic pockets of 2Z63.pdb.pdb. Root mean square deviation of celastrol/2Z63 was in the range of 1.8–4.8 Å.Conclusion In particular, Glu376 of TLR4 receptor is crucial for the identification and binding of lipopolysaccharides (LPS), which are part of Gram-negative bacteria’s outer membrane. In our investigation, celastrol binds to Glu376, suggesting that celastrol may prevent the dry eye syndrome by inhibiting LPS’s binding to TLR4. |
| format | Article |
| id | doaj-art-f65999b201784240b5b57c280cd7a636 |
| institution | Kabale University |
| issn | 2397-3269 |
| language | English |
| publishDate | 2024-05-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | BMJ Open Ophthalmology |
| spelling | doaj-art-f65999b201784240b5b57c280cd7a6362025-02-06T11:55:08ZengBMJ Publishing GroupBMJ Open Ophthalmology2397-32692024-05-019110.1136/bmjophth-2023-001610Unveiling molecular insights: in silico exploration of TLR4 antagonist for management of dry eye syndromeKothandan Sudhakar0Neeru Dugar1Srikanth Jupudi2Ravichandran Ashwin3Kuppusamy Gowthamarajan4Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty,The Nilgiris-643001, Tamil Nadu, IndiaDepartment of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, The Nilgiris-643001, Tamil Nadu, IndiaDepartment of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, The Nilgiris-643001, Tamil Nadu, IndiaDepartment of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty,The Nilgiris-643001, Tamil Nadu, IndiaDepartment of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty,The Nilgiris-643001, Tamil Nadu, IndiaBackground Dry eye disease is the most commonplace multifractional ocular complication, which has already affected millions of people in the world. It is identified by the excessive buildup of reactive oxygen species, leading to substantial corneal epithelial cell demise and ocular surface inflammation attributed to TLR4. In this study, we aimed to identify potential compounds to treat of dry eye syndrome by exploring in silico methods.Methods In this research, molecular docking and dynamics simulation tests were used to examine the effects of selected compounds on TLR4 receptor. Compounds were extracted from different databases and were prepared and docked against TLR4 receptor via Autodock Vina. Celastrol, lumacaftor and nilotinib were selected for further molecular dynamics studies for a deeper understanding of molecular systems consisting of protein and ligands by using the Desmond module of the Schrodinger Suite.Results The docking results revealed that the compounds are having binding affinity in the range of −5.1 to −8.78 based on the binding affinity and three-dimensional interactions celastrol, lumacaftor and nilotinib were further studied for their activity by molecular dynamics. Among the three compounds, celastrol was the most stable based on molecular dynamics trajectory analysis from 100 ns in the catalytic pockets of 2Z63.pdb.pdb. Root mean square deviation of celastrol/2Z63 was in the range of 1.8–4.8 Å.Conclusion In particular, Glu376 of TLR4 receptor is crucial for the identification and binding of lipopolysaccharides (LPS), which are part of Gram-negative bacteria’s outer membrane. In our investigation, celastrol binds to Glu376, suggesting that celastrol may prevent the dry eye syndrome by inhibiting LPS’s binding to TLR4.https://bmjophth.bmj.com/content/9/1/e001610.full |
| spellingShingle | Kothandan Sudhakar Neeru Dugar Srikanth Jupudi Ravichandran Ashwin Kuppusamy Gowthamarajan Unveiling molecular insights: in silico exploration of TLR4 antagonist for management of dry eye syndrome BMJ Open Ophthalmology |
| title | Unveiling molecular insights: in silico exploration of TLR4 antagonist for management of dry eye syndrome |
| title_full | Unveiling molecular insights: in silico exploration of TLR4 antagonist for management of dry eye syndrome |
| title_fullStr | Unveiling molecular insights: in silico exploration of TLR4 antagonist for management of dry eye syndrome |
| title_full_unstemmed | Unveiling molecular insights: in silico exploration of TLR4 antagonist for management of dry eye syndrome |
| title_short | Unveiling molecular insights: in silico exploration of TLR4 antagonist for management of dry eye syndrome |
| title_sort | unveiling molecular insights in silico exploration of tlr4 antagonist for management of dry eye syndrome |
| url | https://bmjophth.bmj.com/content/9/1/e001610.full |
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