ArticlePLoS computational biology2017
Cheminformatics-aided discovery of small-molecule Protein-Protein Interaction (PPI) dual inhibitors of Tumor Necrosis Factor (TNF) and Receptor Activator of NF-κB Ligand (RANKL).
Article in PLoS computational biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 67 citations in OpenAlex.
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- Development of a Robust Read-Across Model for the Prediction of Biological Potency of Novel Peroxisome Proliferator-Activated Receptor Delta Agonists.International journal of molecular sciences · 2024Article
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- 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 · 2021Article
- Identification of novel inhibitors of Keap1/Nrf2 by a promising method combining protein-protein interaction-oriented library and machine learning.Scientific reports · 2021Article
- Therapeutic potential of TNFα inhibitors in chronic inflammatory disorders: Past and future.Genes & diseases · 2021Review
- Rheumatoid Arthritis: Applicability of Ready-to-Use Human Cartilaginous Cells for Screening of Compounds with TNF-Alpha Inhibitory Activity.Biomolecules · 2020Article
- Virtual Prediction of the Delphinidin-3-O-glucoside and Peonidin-3-O-glucoside as Anti-inflammatory of TNF-α Signaling.Acta informatica medica : AIM : journal of the Society for Medical Informatics of Bosnia & Herzegovina : casopis Drustva za medicinsku informatiku BiH · 2019Article
- In Silico Prediction of Drug-Induced Liver Injury Based on Ensemble Classifier Method.International journal of molecular sciences · 2019Article
- ImmtorLig_DB: repertoire of virtually screened small molecules against immune receptors to bolster host immunity.Scientific reports · 2019Article
- Dysregulated Up-Frameshift Protein 1 Promotes Ulcerative Colitis Pathogenesis Through the TNFR1-NF-κB/MAPKs Pathway.Digestive diseases and sciences · 2018Article
- Assessing the Effects of Alloxydim Phototransformation Products by QSAR Models and a Phytotoxicity Study.Molecules (Basel, Switzerland) · 2018Article
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We present an in silico drug discovery pipeline developed and applied for the identification and virtual screening of small-molecule Protein-Protein Interaction (PPI) compounds that act as dual inhibitors of TNF and RANKL through the trimerization interface. The cheminformatics part of the pipeline was developed by combining structure-based with ligand-based modeling using the largest available set of known TNF inhibitors in the literature (2481 small molecules). To facilitate virtual screening, the consensus predictive model was made freely available at: http://enalos.insilicotox.com/TNFPubChem/. We thus generated a priority list of nine small molecules as candidates for direct TNF function inhibition. In vitro evaluation of these compounds led to the selection of two small molecules that act as potent direct inhibitors of TNF function, with IC50 values comparable to those of a previously-described direct inhibitor (SPD304), but with significantly reduced toxicity. These molecules were also identified as RANKL inhibitors and validated in vitro with respect to this second functionality. Direct binding of the two compounds was confirmed both for TNF and RANKL, as well as their ability to inhibit the biologically-active trimer forms. Molecular dynamics calculations were also carried out for the two small molecules in each protein to offer additional insight into the interactions that govern TNF and RANKL complex formation. To our knowledge, these compounds, namely T8 and T23, constitute the second and third published examples of dual small-molecule direct function inhibitors of TNF and RANKL, and could serve as lead compounds for the development of novel treatments for inflammatory and autoimmune diseases.
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