Question 2 of 6 Intermediate Scenario
How would you prioritize two active compounds with different potency and solubility?
Short answer
Compare compounds using meaningful free exposure, cellular activity, selectivity, solubility and assay validity rather than choosing the lowest biochemical IC50 by itself.
Why
Confirm identity and purity, repeat concentration-response curves and check for aggregation or readout interference. Then measure kinetic or biochemical potency under matched conditions and test cellular engagement at achievable unbound concentrations. A nominally 10 nM inhibitor that precipitates before reaching cells may be a worse starting point than a soluble 100 nM inhibitor with reliable target engagement.
Inspect permeability, metabolic stability, off-target activity and opportunities for chemical optimization. Evaluate whether the selected assay reflects the desired mechanism: an enzyme IC50 is sensitive to substrate and assay settings, and a cell EC50 includes transport and cellular biology. Build a multi-parameter decision table and report uncertainty rather than turning one metric into a universal ranking.
If the candidates target a difficult disease site, accessible tissue exposure could dominate potency.
Common mistakes
- Ranking hits solely by a smaller IC50 even when solubility and cellular exposure differ strongly
The interviewer might ask next
Which experiment would distinguish poor permeability from weak intrinsic target binding?