Advantages
Efficient sampling of chemical space
A diverse set of 1000 fragments represents its chemical space about as
effectively as would 10 trillion diverse drug-sized molecules
Ideally suited for PPIs
They can bind to small pockets available on the protein surface
Predictor of protein druggability
Obtaining high hit rates (> 3%) is an excellent predictor that high-affinity, small molecule
ligands can be identified. Low hit rates (< 0.1%) strongly suggest an undruggable pocket
Offer unique binding profiles
High-quality interactions between fragment and target
Chemical optimization
Ability to optimize pharmacokinetics profile simultaneously with potency
as fragment hit grows to clinical candidate
What can we offer on the FBDD platform?
Library
WuXi AppTec fragment library (~3100)
Manually curated by experts in medicinal chemistry
- Approx. 3,100 fragments
- Key pharmacophores
- Appropriate complexity
- Synthetically accessible
- “Rule-of-three” compliant
- PAIN, REOS, SMART filter
PROPERTY
clogP
MW
HAC
HBA
HBD
PSA
RC
RB
CAPABILITY
Biacore 8K
- Screening & kinetic characterization
- 8 channels HTS system
- >1000 compounds / day
- dissociation rates: 10-6 to 0.5 s-1
- affinity range: pM – mM
- kinetic characterization of 64 interactions in 4h
Monolith NT.Automated
- Fully automated MST Screening Unit
- labeled & labelfree MST
- Kd range: pM – mM
- 500-800 compounds / day
- 80 Kd per day
Dianthus NT.23 PicoDuo
- 384 Plate format
- HTS Screening Unit
- KD range: 10 pM – mM
- 1500 Cps/Day (Single Concentration)
- > 150 Full KDs/Day
CASE STUDY
Assay Development and Primary Screening
Hit confirmation – KD ranking
Orthogonal validation
X-Ray Crystallography
Establishment of Soaking system
Fragment Soaking
Automated data processing
Manual refinement of chosen hits
Structure-led fragment-to-hit series development