PMID- 19621420
OWN - NLM
STAT- MEDLINE
DCOM- 20100302
LR  - 20171116
IS  - 1099-1352 (Electronic)
IS  - 0952-3499 (Linking)
VI  - 23
IP  - 1
DP  - 2010 Jan-Feb
TI  - Organic dyes as small molecule protein-protein interaction inhibitors for the 
      CD40-CD154 costimulatory interaction.
PG  - 65-73
LID - 10.1002/jmr.969 [doi]
AB  - It is becoming increasingly clear that small molecules can often act as effective 
      protein-protein interaction (PPI) inhibitors, an area of increasing interest for 
      its many possible therapeutic applications. We have identified several organic 
      dyes and related small molecules that (i) concentration-dependently inhibit the 
      important CD40-CD154 costimulatory interaction with activities in the low 
      micromolar (microM) range, (ii) show selectivity toward this particular PPI, 
      (iii) seem to bind on the surface of CD154, and (iv) concentration-dependently 
      inhibit the CD154-induced B cell proliferation. They were identified through an 
      iterative activity screening/structural similarity search procedure starting with 
      suramin as lead, and the best smaller compounds, the main focus of the present 
      work, achieved an almost 3-fold increase in ligand efficiency 
      (DeltaG(0)/nonhydrogen atom = 0.8 kJ/N(nHa)) approaching the average of known 
      promising small-molecule PPI inhibitors (approximately 1.0 kJ/N(nHa)). Since 
      CD154 is a member of the tumor necrosis factor (TNF) superfamily of cell surface 
      interaction molecules, inhibitory activities on the TNF-R1-TNF-alpha interactions 
      were also determined to test for specificity, and the compounds selected here all 
      showed more than 30-fold selectivity toward the CD40-CD154 interaction. Because 
      of their easy availability in various structural scaffolds and because of their 
      good protein-binding ability, often explored for tissue-specific staining and 
      other purposes, such organic dyes can provide a valuable addition to the chemical 
      space searched to identify small molecule PPI inhibitors in general.
CI  - (c) 2009 John Wiley & Sons, Ltd.
FAU - Buchwald, Peter
AU  - Buchwald P
AD  - Diabetes Research Institute, Miller School of Medicine, University of Miami, 
      Miami, Florida 33136, USA. pbuchwald@med.miami.edu
FAU - Margolles-Clark, Emilio
AU  - Margolles-Clark E
FAU - Kenyon, Norma S
AU  - Kenyon NS
FAU - Ricordi, Camillo
AU  - Ricordi C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Mol Recognit
JT  - Journal of molecular recognition : JMR
JID - 9004580
RN  - 0 (CD40 Antigens)
RN  - 0 (Coloring Agents)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type I)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 147205-72-9 (CD40 Ligand)
RN  - 6032D45BEM (Suramin)
SB  - IM
MH  - B-Lymphocytes/cytology/drug effects/metabolism
MH  - CD40 Antigens/chemistry/*metabolism
MH  - CD40 Ligand/chemistry/*metabolism
MH  - Cell Proliferation/drug effects
MH  - Coloring Agents/*chemistry
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Protein Binding/physiology
MH  - Receptors, Tumor Necrosis Factor, Type I/chemistry/metabolism
MH  - Suramin/chemistry/*metabolism
MH  - Tumor Necrosis Factor-alpha/chemistry/metabolism
EDAT- 2009/07/22 09:00
MHDA- 2010/03/03 06:00
CRDT- 2009/07/22 09:00
PHST- 2009/07/22 09:00 [entrez]
PHST- 2009/07/22 09:00 [pubmed]
PHST- 2010/03/03 06:00 [medline]
AID - 10.1002/jmr.969 [doi]
PST - ppublish
SO  - J Mol Recognit. 2010 Jan-Feb;23(1):65-73. doi: 10.1002/jmr.969.