BioUnfold #2 — Phenotypic vs Target-Based Screening
Drug discovery begins with a philosophical choice: do you define the problem or observe it first? Most teams pick one. The best programs combine both.
Target-based discovery
A target-based strategy starts with a known mechanism.
If two proteins should interact and one is misfolded in patients, chemists can design a molecule to restore binding.
This path is structured: identify, model, optimize, test. Much of the early work can occur in silico, and progress is easy to measure. That clarity explains why most funded programs follow it.
The kinase inhibitors of the 1990s — starting with imatinib — are classic examples: clear mechanism, tractable chemistry, reproducible assays.
Phenotypic discovery
A phenotypic strategy begins with observation: a transcriptional, morphological, or behavioral change in a system.
Scientists reproduce the phenotype experimentally and test interventions that restore normal function.
This path is less defined but more open to unexpected biology. Many first-in-class drugs — including statins and aripiprazole — were identified this way, with mechanisms clarified later. Because biology is redundant, phenotypic screening can expose alternative control points that targeted campaigns might miss.
The trade-off
Target-based programs optimize for clarity; phenotypic programs optimize for discovery.
Mechanistic clarity accelerates development but can create blind spots.
Phenotypic breadth reveals surprises but makes optimization harder.
AI now touches both modes — predicting targets from omics and structure, or classifying and ranking phenotypic responses from images and signals. But the real challenge stays the same: knowing when correlation implies causation.
The real take
These two approaches are not in competition. The smartest teams decide when to bring them together, not which one to abandon.
Relying only on targets makes you efficient but narrow.
Relying only on phenotypes makes you curious but slow.
Balancing both makes discovery powerful.
Additional reading
- “Phenotypic Screening in the Era of Mechanism-Based Drug Discovery” — Nature Reviews Drug Discovery (2022).
Read on PubMed Central
A concise overview of how modern phenotypic and target-based paradigms can converge, with examples across therapeutic areas.
h/t Ronen Schuster
Edited on 31 Oct 2025 — added Additional Reading section with reference and credit.