4.7 Article

Structural Basis of Small-Molecule Aggregate Induced Inhibition of a Protein Protein Interaction

Journal

JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 8, Pages 3511-3517

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b01836

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Funding

  1. Janssen Research & Development, LLC.

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A prevalent observation in high-throughput screening and drug discovery programs is the inhibition of protein function by small-molecule compound aggregation. Here, we present-the X-ray structural description of aggregation-based inhibition of a protein protein interaction involving tumor necrosis factor alpha (TNF alpha). An ordered conglomerate of an aggregating small-mUlecule inhibitor (JNJ525) induces a qUaternary structure switch of TNF alpha that inhibits the protein-protein interaction between TNF alpha and TNF alpha receptors. SPD-304 may employ a similar mechanism of inhibition.

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