#11thICCS Henriëtte Willems on Strategies for assembling an annotated library for phenotypic screening
Phenotypic screening is an alternative to target-based drug discovery. Could have high-content imaging screen, find phenotypic hits, then find the target/biology.
Instead could base it on a pathway
Has been v successful in the past. 28 out of 50 first in class FDA approved small mols have come from this.
Has been v successful in the past. 28 out of 50 first in class FDA approved small mols have come from this.
Disease relevant, greater conf that hits will deliver the desired therapeutic effect. But difficult to derive SAR, and so mostly you want to know the target and so have to find it out somehow.
Which cmpds to screen? Usually relatively small nos of cmpds, with well-annotated pharmacology. SGC has criteria for tool cmpds - but quite stringent. "Orthogonal" chemical problems, diff chemical structures with act for same target (likely to have different off-target)
Dark chemical matter - might have hit, but wouldn't know why.
ARUK (Alzheimer's Res UK) approach in collab with LifeArc. Started by mining ChEMBL. Then looking at availability by SPECS there were 5K cmpds.
Wanted selective cmpds but hard to decide on which are selective. What's an acceptable ration between activity on off-targets and targets. Absolute or relative potency? Similar targets vs different targets? What about if you don't know the subtype activity (e.g. some Chembl data
Used Windows score (Bosc BMC Bioing 2017 18 17). How many targets are hit in a particular window of activity relative to the primary potency.
We ended up defining three groups of cmpds. Green: active for 1 and inactive/weakly active for at least one other. Blue and Yellow groups also based on number of off targets and potency differences.
Some issues: protein targets for diff species have diff identifiers (ChEMBL ids not sufficient). Transportes and Cyps were included. Duplicate cmpds.
Workflow all implemented in Knime. MedChem Express and SPECS were searched for availability. MCE affordable and SPECS sources from diff vendors.
LifeArc had an existing phenotypic library. Partly based on similarity, so did not have ChEMBL annotation. Chemical Probes website and various vendor websites are not set up to search with lists of molecules.
Some troublesome cmpds shown. It's in ChEMBL, but via PubChem assay and acitivity comment: "inconclusive". An example of an approved drug, but not target associated. No mamallian protein target for another. Another inhibits a whole family of proteins.
Some examples of well annotated and selective cmpds in ChEMBL. Hydroquinone? Amantadine? Pepcid?
We wanted to cover a broad range of protein families. Shows ring plot. Seems like good coverage. Which targets not covered? There were gaps - needed to go back and fill them. Where else to look? Difficult to mine SureCHEMBL for non specialist.
Look to PDB? Molport and MCule - good portals with lists of SMILES. Knime nodes to search. Custom synthesis? Too time-consuming and expensive.
Discussed Including cmpds of same chemotypes as actives to help deconvolute targets (controls). Currently looking to investigate other vendors. Also thinking more about 'dark chemical matter'.
