Substituted 1,4-benzodiazepine-2,5-diones as alpha-helix mimetic antagonists of the HDM2-p53 protein-protein interaction.
Small molecule antagonists of protein-protein interactions represent a particular challenge for pharmaceutical discovery. One approach to finding molecules that can disrupt these interactions is to seek mimics of common protein structure motifs. We present an analysis of how molecules based on the 1,4-benzodiazepine-2,5-dione scaffold serve to mimic the side-chains presented by the hydrophobic face of two turns of an alpha-helix derived from the tumor suppressor protein p53, and thus antagonize the HDM2-p53 protein-protein binding interaction.
Cummings
Maxwell D
MD
Johnson & Johnson Pharmaceutical Research & Development, Exton, PA 19341, USA. mcumming@prdus.jnj.com
Schubert
Carsten
C
Parks
Daniel J
DJ
Calvo
Raul R
RR
LaFrance
Louis V
LV
Lattanze
Jennifer
J
Milkiewicz
Karen L
KL
Lu
Tianbao
T
D001569:Benzodiazepines / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D018716:Molecular Mimicry; D025941:Protein Interaction Mapping; D017433:Protein Structure, Secondary / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D001569:Benzodiazepines; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C468549:Bz-423