Designing novel inhibitors of transcription factor BRD4
Utilizing Receptor.AI’s hit identification workflow to target member of a family of 4 similar proteins
3.2M
compounds
screened
100
hit candidates
selected
17
compounds with high
affinity to BRD4
3
potent hits
identified
01/ Background
- The target is Human Bromodomain-containing protein 4 (BRD4) — transcription factor with an important role in cancer development.
- BRD4 is a member of a family of at least four proteins sharing the same structural motif.
02/ Methodology
- 3.2M compounds were prefiltered from 8M stock library based on 16 psychem/druglike filters.
- Using target’s protein data, compounds were subjected to
semi-ligand DTI model scoring. - Evaluated the most relevant ADMET endpoints.
- Performed proteome-wide selectivity scoring.
- ~50K ligands subjected to ArtiDock AI docking and AI rescoring.
- 100 compounds selected for in vitro validation from 1000 best using AI-guided hit candidates selection.
- Experimental validation was performed using a
differential scanning fluorimetry assay.
03/ Results
- 17 compounds demonstrated a significant binding effect.
- 8 of them belong to known classes of BRD4 inhibitors.
- 9 hits are entirely new to BRD4, representing 8 chemical classes.
*Difference between BRD4-control and
BRD4-ligand complex melting temperatures
BRD4-ligand complex melting temperatures
04/ Best Compound
- Previously unknown class of BRD4 inhibitors.
- Has shown the highest potency in experiments (IC50 = 470 nM).
