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BMJ Open Ophthalmol ; 9(1)2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38702178

RESUMO

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.


Assuntos
Síndromes do Olho Seco , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Triterpenos Pentacíclicos , Pirimidinas , Receptor 4 Toll-Like , Síndromes do Olho Seco/tratamento farmacológico , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/química , Humanos , Triterpenos Pentacíclicos/farmacologia , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/química , Pirimidinas/uso terapêutico , Triterpenos/farmacologia , Triterpenos/química , Simulação por Computador , Ligantes , Aminopiridinas/farmacologia , Aminopiridinas/química , Aminopiridinas/uso terapêutico
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