Exploring the natural chemiome to target interleukin-6 receptor (IL-6R) cytokines: an atomic scale investigation for novel rheumatoid arthritis drug discovery

Abstract

Natural compounds are a gold mine for treating rheumatoid arthritis (RA). The etiology of this disease is linked to inflammation, where cytokines play an important role. Strategies have been drafted for targeting cytokines as a therapeutic option in patients with RA. Inhibiting cytokines with natural compounds has become a major focus for the development of drugs to treat RA. Here, a structure-based drug design approach was employed to identify novel leads to target the interleukin 6 receptor (IL-6R). A total of 48,531 compounds of natural origin were screened. Two of these compounds were shortlisted for molecular docking simulation and tested for inhibiting gp130 dimerization in human macrophages. The results show that Lead5 (CID5329098) significantly inhibited the release of gp130 in a dose-dependent manner, similar to the inhibitory effect of . This study provides an atomic scale outcome of a single natural compound that can be developed into a RA drug.

Bioflavonoid Robinin from Astragalus falcatus Lam. Mildly Improves the Effect of Metothrexate in Rats with Adjuvant Arthritis

“…Suppressing cytokines with natural products has become an important focus in the development of new drugs to treat RA [47]. Inflammatory processes in RA, such as swelling of the synovium of the joint, with subsequent destruction of articular structures are associated with activation of synovial fibroblasts and Th-lymphocytes [48].…”

Molecular Docking and Molecular Dynamics Aided Virtual Search of OliveNet™ Directory for Secoiridoids to Combat SARS-CoV-2 Infection and Associated Hyperinflammatory Responses

“…Methotrexate can directly inhibit the binding of IL1β to IL1R, resulting in inhibition of IL1β mediated cellular responses (Brody et al, 1993 ). A small-molecule inhibitor of IL6R, Chemiome CID5329098 (Chen et al, 2017 ), was used as the reference molecule for IL6R inhibition. Physcion-8-glucoside is an inhibitor of TNFR1 (Saddala and Huang, 2019 ), used as the reference molecule for TNFR1 inhibition.…”

“…It is of paramount importance to block the actions of inflammatory cytokines to improve the patient's well-being and reduce the fatality rate of SARS-COV-2 infected patients. The receptors IL1R (Maiti et al, 2020 ), IL6R (Chen et al, 2017 ), and TNFR1 (Maiti et al, 2020 ) of cytokines are useful targets to evaluate the anti-inflammatory potential of secoiridoids.…”

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“…Methotrexate can directly inhibit the binding of IL1β to IL1R, resulting in inhibition of IL1β mediated cellular responses (Brody et al, 1993). A small-molecule inhibitor of IL6R, Chemiome CID5329098 (Chen et al, 2017), was used as the reference molecule for IL6R inhibition. Physcion-8-glucoside is an inhibitor of TNFR1 (Saddala and Huang, 2019), used as the reference molecule for TNFR1 inhibition.…”