12 research outputs found

    Cheminformatics-aided discovery of small-molecule Protein-Protein Interaction (PPI) dual inhibitors of Tumor Necrosis Factor (TNF) and Receptor Activator of NF-ÎşB Ligand (RANKL)

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    <div><p>We present an <i>in silico</i> 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: <a href="http://enalos.insilicotox.com/TNFPubChem/" target="_blank">http://enalos.insilicotox.com/TNFPubChem/</a>. We thus generated a priority list of nine small molecules as candidates for direct TNF function inhibition. <i>In vitro</i> evaluation of these compounds led to the selection of two small molecules that act as potent direct inhibitors of TNF function, with IC<sub>50</sub> 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 <i>in vitro</i> 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.</p></div

    Optimization of Non-ATP Competitive CDK/Cyclin Groove Inhibitors through REPLACE-Mediated Fragment Assembly

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    A major challenge in drug discovery is to develop and improve methods for targeting protein–protein interactions. Further exemplification of the REPLACE (REplacement with Partial Ligand Alternatives through Computational Enrichment) strategy for generating inhibitors of protein–protein interactions demonstrated that it can be used to optimize fragment alternatives of key determinants, to combine these in an effective way, and this was achieved for compounds targeting the cyclin-dependent kinase 2 (CDK2) substrate recruitment site on the cyclin regulatory subunit. Phenylheterocyclic isosteres replacing a critical charge–charge interaction provided new structural insights for binding to the cyclin groove. In particular, these results shed light onto the key contributions of a H-bond observed in crystal structures of N-terminally capped peptides. Furthermore, the structure–activity relationship of a bis­(aryl) ether C-terminal capping group mimicking dipeptide interactions was probed through ring substitutions, allowing increased complementarity with the primary hydrophobic pocket. This study further validates REPLACE as an effective strategy for converting peptidic compounds to more pharmaceutically relevant compounds

    Ligand–based predictions through the Enalos cloud platform (http://enalos.insilicotox.com/TNFPubChem/), Tanimoto similarity to SPD304, PAINS check.

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    <p>Ligand–based predictions through the Enalos cloud platform (<a href="http://enalos.insilicotox.com/TNFPubChem/" target="_blank">http://enalos.insilicotox.com/TNFPubChem/</a>), Tanimoto similarity to SPD304, PAINS check.</p