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Underpinning Endogeneous Damp EDA-Fibronectin in the Activation of Molecular Targets of Rheumatoid Arthritis and Identifcation of its Effective Inhibitors by Computational Methods

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Abstract

Rheumatoid arthritis (RA) is one of the most severe inflammatory diseases that cause swelling, stiffness and pain in the joints, which pose a significant threat worldwide. Damage-associated molecular patterns (DAMPs) are danger molecules of endogenous origin, released during cell injury or cell death, interacts with various Pattern recognition receptors (PRRs) and activates various inflammatory diseases. One of the DAMP molecules, so-called EDA-fibronectin (Fn) is also responsible for causing RA. EDA-Fn triggers RA through its interaction with TLR4. Apart from TLR4, it is divulged that certain other PRR’s are also responsible for RA, but the identity and mechanism of those PRRs remain unknown until now. Hence, for the first time, we tried to reveal those PRR’s interaction with EDA-Fn in RA through computational methods. Protein–protein interaction (PPI) was checked using ClusPro between EDA-Fn and certain Pattern recognition receptors (PRRs) to explore the binding affinities of the potential PRRs. Protein–protein docking unveiled that TLR5, TLR2 and RAGE has good interaction with EDA-Fn than the well-reported TLR4. Macromolecular simulation was performed for TLR5, TLR2 and RAGE complexes along with the control group TLR4 for 50 ns to further investigate the stability, leading to the identification of TLR2, TLR5 and RAGE as the stable complexes. Hence, TLR2, TLR5 and RAGE on interaction with EDA-Fn may lead to the progression of RA that may need additional validations through in vitro and in vivo animal models. Molecular docking was used to analyse the binding force of the top 33 active anti-arthritic compounds with the target protein EDA-Fn. Molecular docking study showed that withaferin A has a good binding activity with EDA-fibronectin target. Hence, it is emphasized that guggulsterone and berberine could modulate the EDA-Fn-mediated TLR5/TLR2/RAGE pathways, thereby it could inhibit the deteriorating effects of RA which needs further in vitro and in vivo experimental validations.

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  1. Department of Pharmaceutical Technology, University College of Engineering, Bharathidasan Institute of Technology Campus, Anna University, Tiruchirappalli, 620 024, Tamil Nadu, India

    Premnath Sakthivel, Indrajith Sakthivel, Sivasakthi Paramasivam, Senthamil Selvan Perumal & Sanmuga Priya Ekambaram

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Premnath Sakthivel: data curation, formal analysis, methodology, software, visualisation, writing—original draft, writing—review and editing. Indrajith Sakthivel: Data curation, formal analysis, methodology, software, visualisation, writing—review and editing. Sivasakthi Paramasivam: data curation, methodology, software, visualisation, writing—review and editing. Senthamil Selvan Perumal: data curation, methodology, software, supervision, writing—review and editing. Sanmuga Priya Ekambaram: conceptualization, investigation, project administration, supervision, validation, writing—review and editing.

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Sakthivel, P., Sakthivel, I., Paramasivam, S. et al. Underpinning Endogeneous Damp EDA-Fibronectin in the Activation of Molecular Targets of Rheumatoid Arthritis and Identifcation of its Effective Inhibitors by Computational Methods. Appl Biochem Biotechnol 195, 7037–7059 (2023). https://doi.org/10.1007/s12010-023-04451-8

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