3.2M
focused library screened
94
hit candidates
selected
5
potent compounds
identified
90 nM
IC50 of the best
compound
01/ Background
- The target is Human Silent Mating Type Information Regulation 2 Homolog 1 (SIRT1).
- SIRT1 deacetylates histones and various other proteins, which are involved in multiple signaling pathways.
02/ Methodology
- 3.2M compounds were prefiltered from 11M stock library based on 16 psychem/druglike filters.
- QuorumMap optimization parameters defined by project input.
- Optimization loop included docking against target and off-targets with ArtiDock and ADME-Tox prediction with ADMTETIQ
- After 100 cycle runs, optimzation reached a plateau.
- 94 compounds were selected for in vitro validation.
- Differential scanning fluorimetry assay performed.
03/ Results
- 4 compounds demonstrated a significant binding effect.
- 1 hit compound shown 3x selectivity against off-targets.
- This hit was subjected to dose-response test in SIRT-Glo assay.
*Difference between SIRT1-control and
SIRT1-ligand complex melting temperatures
SIRT1-ligand complex melting temperatures
04/ Best Compound
- This compound has shown outstanding nanomolar activity
(IC50 = 90 nM) measured by a functional assay based on the release of the fluorophore probe from acetylated p53-AFC. - This makes it de facto a lead compound.
