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

Autor: Blevitt JM; Emerging Science & Innovation, Discovery Sciences, Janssen R&D LLC , La Jolla, California 92121, United States., Hack MD; Lead Discovery, Discovery Sciences, Janssen R&D LLC , La Jolla, California 92121, United States., Herman KL; Emerging Science & Innovation, Discovery Sciences, Janssen R&D LLC , La Jolla, California 92121, United States., Jackson PF; Emerging Science & Innovation, Discovery Sciences, Janssen R&D LLC , La Jolla, California 92121, United States., Krawczuk PJ; Immunology, Janssen R&D LLC , Spring House, Pennsylvania 19477, United States., Lebsack AD; Immunology, Janssen R&D LLC , La Jolla, California 92121, United States., Liu AX; Emerging Science & Innovation, Discovery Sciences, Janssen R&D LLC , Spring House, Pennsylvania 19477, United States., Mirzadegan T; Lead Discovery, Discovery Sciences, Janssen R&D LLC , La Jolla, California 92121, United States., Nelen MI; Lead Discovery, Discovery Sciences, Janssen R&D LLC , Spring House, Pennsylvania 19477, United States., Patrick AN; Emerging Science & Innovation, Discovery Sciences, Janssen R&D LLC , Spring House, Pennsylvania 19477, United States., Steinbacher S; Proteros Biostructures , 82152 Martinsried, Germany., Milla ME; Emerging Science & Innovation, Discovery Sciences, Janssen R&D LLC , La Jolla, California 92121, United States., Lumb KJ; Emerging Science & Innovation, Discovery Sciences, Janssen R&D LLC , Spring House, Pennsylvania 19477, United States.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2017 Apr 27; Vol. 60 (8), pp. 3511-3517. Date of Electronic Publication: 2017 Mar 16.
DOI: 10.1021/acs.jmedchem.6b01836
Abstrakt: 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 α (TNFα). An ordered conglomerate of an aggregating small-molecule inhibitor (JNJ525) induces a quaternary structure switch of TNFα that inhibits the protein-protein interaction between TNFα and TNFα receptors. SPD-304 may employ a similar mechanism of inhibition.
Databáze: MEDLINE
Externí odkaz: