+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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)

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)

Plos Computational Biology 13(4): E1005372

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.

Please choose payment method:

(PDF emailed within 1 workday: $29.90)

Accession: 059493760

Download citation: RISBibTeXText

PMID: 28426652

Related references

Current Status and Future Prospects of Small-molecule Protein-protein Interaction (PPI) Inhibitors of Tumor Necrosis Factor (TNF) and Receptor Activator of NF-κB Ligand (RANKL). Current Topics in Medicinal Chemistry 18(8): 661-673, 2018

In Silico Discovery of Plant-Origin Natural Product Inhibitors of Tumor Necrosis Factor (TNF) and Receptor Activator of NF-κB Ligand (RANKL). Frontiers in Pharmacology 9: 800, 2018

Development of Small Molecules Targeting Receptor Activator of Nuclear Factor-κB Ligand (RANKL) - Receptor Activator of Nuclear Factor-κB (RANK) Protein-Protein Interaction by Structure-Based Virtual Screening and Hit Optimization. Journal of Medicinal Chemistry 2019, 2019

Screening bicyclic peptide libraries for protein-protein interaction inhibitors: discovery of a tumor necrosis factor-α antagonist. Journal of the American Chemical Society 135(32): 11990-5, 2014

Discovery of Selective Small-Molecule Inhibitors for the β-Catenin/T-Cell Factor Protein-Protein Interaction through the Optimization of the Acyl Hydrazone Moiety. Journal of Medicinal Chemistry 58(11): 4678-4692, 2015

Development and ligand-protein interaction of small molecule anti-tumor FGFR inhibitors. Yao Xue Xue Bao 51(11): 1689-1697, 2018

Discovery of small molecule inhibitors of protein-protein interactions using combined ligand and target score normalization. Journal of Chemical Information and Modeling 49(12): 2708-2717, 2010

Expression of receptor activator of nuclear factor kappabeta ligand (RANKL) and tumour necrosis factor related, apoptosis inducing ligand (TRAIL) in breast cancer, and their relations with osteoprotegerin, oestrogen receptor, and clinicopathological variables. Journal of Clinical Pathology 59(7): 716-720, 2006

Soluble glucocorticoid-induced tumor necrosis factor receptor (sGITR) stimulates osteoclast differentiation in response to receptor activator of NF-kappaB ligand (RANKL) in osteoclast cells. Bone 36(5): 832-839, 2005

Discovery of 5-(2',4'-difluorophenyl)-salicylanilides as new inhibitors of receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis. European Journal of Medicinal Chemistry 98: 115-126, 2016

Pharmacophore Modelling as a Virtual Screening Tool for the Discovery of Small Molecule Protein-protein Interaction Inhibitors. Current Pharmaceutical Design 18(30): 4586-4598, 2012

HIV Envelope gp120-mediated Regulation of Osteoclastogenesis via Receptor Activator of Nuclear Factor kB Ligand (RANKL) Secretion and Its Modulation by Certain HIV Protease Inhibitors through Interferon-c/RANKL Cross-talk. The Journal of Biological Chemistry 278(48): 251-8, 2003

NF-kappaB p50 and p52 regulate receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1. Journal of Biological Chemistry 282(25): 18245-18253, 2007

Discovery of indeno[1,2-c]quinoline derivatives as inhibitors of osteoclastogenesis induced by receptor activator of NF-κB ligand (RANKL). Journal of Medicinal Chemistry 54(8): 3103-3107, 2011

HIV envelope gp120-mediated regulation of osteoclastogenesis via receptor activator of nuclear factor kappa B ligand (RANKL) secretion and its modulation by certain HIV protease inhibitors through interferon-gamma/RANKL cross-talk. Journal of Biological Chemistry 278(48): 48251-8, 2003