Abstract
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 (mM) 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 (ΔG0/nonhydrogen atom 1/40.8 kJ/NnHa) approaching the average of known promising small-molecule PPI inhibitors (~1.0 kJ/NnHa). Since CD154 is a member of the tumor necrosis factor (TNF) superfamily of cell surface interaction molecules, inhibitory activities on the TNF-R1-TNF-a 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.
| Original language | English |
|---|---|
| Pages (from-to) | 65-73 |
| Number of pages | 9 |
| Journal | Journal of Molecular Recognition |
| Volume | 23 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2010 |
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Keywords
- Binding free energy
- CD40 ligand
- Costimulation
- Immune suppression
- Protein-protein interaction
ASJC Scopus subject areas
- Molecular Biology
- Structural Biology
Cite this
Organic dyes as small molecule protein-protein interaction inhibitors for the CD40-CD154 costimulatory interaction. / Buchwald, Peter; Margolles-Clark, Emilio; Kenyon, Norma S; Ricordi, Camillo.
In: Journal of Molecular Recognition, Vol. 23, No. 1, 01.01.2010, p. 65-73.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Organic dyes as small molecule protein-protein interaction inhibitors for the CD40-CD154 costimulatory interaction
AU - Buchwald, Peter
AU - Margolles-Clark, Emilio
AU - Kenyon, Norma S
AU - Ricordi, Camillo
PY - 2010/1/1
Y1 - 2010/1/1
N2 - 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 (mM) 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 (ΔG0/nonhydrogen atom 1/40.8 kJ/NnHa) approaching the average of known promising small-molecule PPI inhibitors (~1.0 kJ/NnHa). Since CD154 is a member of the tumor necrosis factor (TNF) superfamily of cell surface interaction molecules, inhibitory activities on the TNF-R1-TNF-a 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.
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 (mM) 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 (ΔG0/nonhydrogen atom 1/40.8 kJ/NnHa) approaching the average of known promising small-molecule PPI inhibitors (~1.0 kJ/NnHa). Since CD154 is a member of the tumor necrosis factor (TNF) superfamily of cell surface interaction molecules, inhibitory activities on the TNF-R1-TNF-a 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.
KW - Binding free energy
KW - CD40 ligand
KW - Costimulation
KW - Immune suppression
KW - Protein-protein interaction
UR - http://www.scopus.com/inward/record.url?scp=73249129041&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=73249129041&partnerID=8YFLogxK
U2 - 10.1002/jmr.969
DO - 10.1002/jmr.969
M3 - Article
C2 - 19621420
AN - SCOPUS:73249129041
VL - 23
SP - 65
EP - 73
JO - Journal of Molecular Recognition
JF - Journal of Molecular Recognition
SN - 0952-3499
IS - 1
ER -