Replication of association of the interleukin 23 receptor rs1343151 variant with rheumatoid arthritis in Caucasian sample sets

Arthritis literally refers “joint inflammation”, it is a condition where one or more joints are inflamed. More than 100 different types of Arthritis were identified, most common types are rheumatoid arthritis and osteoarthritis. The present study mainly focuses on the development of the novel phytochemical inhibitors against rheumatoid arthritis and osteoarthritis using an integrative cheminformatics drug discovery platform. In this study, we identified potential 405 phytochemical drug candidates, screened against eight selected targets of rheumatoid arthritis and osteoarthritis using molecular docking tool AutoDock. Three phytochemicals Withanolide, Diosgenin and bamyrin exhibited promising binding towards multiple drug targets selected for this study. When comparing with the binding between reference drugs, withanolide showed highest activity against Interleukin-23, Matrix metalloproteinase-3 and Interleukin 8 with binding energies -11.6, -9.4 and -8.3 kcal/mol respectively. Diosgenin also exhibited best activity against three targets that were Interleukin-23, JNK alpha and MMP-3 with -11.3, -10.4, -9.5 kcal/mol binding energies respectively. This study may be important contributing factor to develop new therapeutic drugs for rheumatoid arthritis and osteoarthritis.

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Designing a new bi-specific tandem single-chain variable fragment antibody against tumor necrosis factor-α and interleukin-23 via in silico studies for the treatment of Rheumatoid arthritis

10.21203/rs.2.23111/v1 ◽

2020 ◽

Author(s):

Asgar Barkhordaria ◽

Karim Mahnam ◽

Hamid Mir Mohammad Sadeghi

Keyword(s):

Rheumatoid Arthritis ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Single Chain Variable Fragment ◽

Single Chain ◽

Rheumatoid Arthritis Disease ◽

Interleukin 23 ◽

Factor Α ◽

Necrosis Factor

Abstract Background: Rheumatoid arthritis disease is a chronic autoimmune inflammatory disease that mainly causes synovial joint inflammation and cartilage destruction. Tumor necrosis factor-α (TNF-α) is a pivotal cytokine that plays an important role in rheumatoid arthritis. The treatments focusing on a single cytokine' inhibition, are able to clinically produce meaningful responses in only about half of the treated patients due to multiple cytokines involved in this disease. In the present study, a bi-specific tandem single-chain variable fragment was designed in order to suppress both human tumor necrosis factor-α and interleukin-23 (IL23) as a potential therapeutic drug candidate for this disease. To do so, at first, eight bi-specific tandem single-chain variable fragment models were built against tumor necrosis factor-α and interleukin-23 cytokines with different domain orders and then 50 ns molecular dynamics simulation was performed for each one and thereafter structural properties were exploited. Results: MD simulation results indicate that the domains' order strongly affects tandem single-chain variable fragment properties and in overall, the fragment VLIL23+Linker+VHIL23+linker+VLTNF+Linker+VHTNF +His6 (VL is variable light and VH is variable heavy fragments and His6 is six histidine) not only separated antibody domains but also had better stability and solvation energy. Conclusions: Hence, this structure can be considered as a potential drug for rheumatoid arthritis. It is hoped that this research could shed a light for the treatment of Rheumatoid arthritis disease.

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