Article ; Online: In Silico Identification and Evaluation of Natural Products as Potential Tumor Necrosis Factor Function Inhibitors Using Advanced Enalos Asclepios KNIME Nodes.
International journal of molecular sciences
2021 Volume 22, Issue 19
Abstract: Tumor necrosis factor (TNF) is a regulator of several chronic inflammatory diseases, such as rheumatoid arthritis. Although anti-TNF biologics have been used in clinic, they render several drawbacks, such as patients' progressive immunodeficiency and ... ...
| Abstract | Tumor necrosis factor (TNF) is a regulator of several chronic inflammatory diseases, such as rheumatoid arthritis. Although anti-TNF biologics have been used in clinic, they render several drawbacks, such as patients' progressive immunodeficiency and loss of response, high cost, and intravenous administration. In order to find new potential anti-TNF small molecule inhibitors, we employed an in silico approach, aiming to find natural products, analogs of Ampelopsin H, a compound that blocks the formation of TNF active trimer. Two out of nine commercially available compounds tested, Nepalensinol B and Miyabenol A, efficiently reduced TNF-induced cytotoxicity in L929 cells and production of chemokines in mice joints' synovial fibroblasts, while Nepalensinol B also abolished TNF-TNFR1 binding in non-toxic concentrations. The binding mode of the compounds was further investigated by molecular dynamics and free energy calculation studies, using and advancing the Enalos Asclepios pipeline. Conclusively, we propose that Nepalensinol B, characterized by the lowest free energy of binding and by a higher number of hydrogen bonds with TNF, qualifies as a potential lead compound for TNF inhibitors' drug development. Finally, the upgraded Enalos Asclepios pipeline can be used for improved identification of new therapeutics against TNF-mediated chronic inflammatory diseases, providing state-of-the-art insight on their binding mode. |
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| MeSH term(s) | Animals ; Anti-Inflammatory Agents/chemistry ; Anti-Inflammatory Agents/pharmacology ; Binding Sites/drug effects ; Biological Products/chemistry ; Biological Products/pharmacology ; Cell Line ; Cell Survival/drug effects ; Computer Simulation ; Drug Design ; Drug Discovery/methods ; Fibroblasts/drug effects ; Mice ; Primary Cell Culture ; Synovial Fluid/drug effects ; Tumor Necrosis Factor Inhibitors/chemistry ; Tumor Necrosis Factor Inhibitors/pharmacology ; Tumor Necrosis Factor-alpha/toxicity |
| Chemical Substances | Anti-Inflammatory Agents ; Biological Products ; Tumor Necrosis Factor Inhibitors ; Tumor Necrosis Factor-alpha |
| Language | English |
| Publishing date | 2021-09-23 |
| Publishing country | Switzerland |
| Document type | Journal Article |
| ZDB-ID | 2019364-6 |
| ISSN | 1422-0067 ; 1422-0067 ; 1661-6596 |
| ISSN (online) | 1422-0067 |
| ISSN | 1422-0067 ; 1661-6596 |
| DOI | 10.3390/ijms221910220 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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