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Drug Discovery → Phenotypic-Based

Phenotypic-based drug discovery (PDD) relies on physiological/phenotypical read-outs against a compound. The major risk associated with this pathway is centered around how well the chosen assay predicts a response in humans.

Drugs typically provide a therapeutic benefit by engaging a molecular target; however, a priori knowledge of that target is not essential. In the case of PDD, a ‘physiologically relevant’ biological system or cellular signaling pathway is directly interrogated by chemical matter to discover biologically active compounds.

Target-based

  • Relies on animal models or cell-based assays
  • Explored complex non-linear pathways of disease

  • Smaller number of compounds are screened against a system that has many targets
  • When the system is exposed to the compounds of interest, a change is phenotype is desired

  • Usually represents the most successful strategy for small-molecule, first-in-class drugs

  • Various methods can be used: affinity chromatography, expression-cloning, protein microarray, ‘reverse transfected’ cell microarray, and biochemical suppression

  • Once pharmacology is understood, the target may be identified
  • Risky to push forward a compound without evaluating the dose-response relationship

Case Study: Lacosamide

Epilepsy is one of the most common neurological disorders and is estimated to affect ~3% of the general population. The disorder encompasses several syndromes, making it difficult to understand the complexity of the system as well as any possible targeting. The most common symptom of epilepsy is a predisposition to recurrent unprovoked seizures. In the mid-80s, rodent models were used to phenotypically screen for possible drug candidates. Two different models relied on rodents with a genetic susceptibility to seizures or were induced seizures either electrically or chemically. Systematic evaluation of more than 100 derivatives of modified alanine amino acid led to the identification of lacosamide. Its precise mechanism of action was unknown at the time of approval (Lacosamide enhances the slow inactivation of voltage-gated sodium channels without affecting the fast inactivation of voltage-gated sodium channels), and the exact amino acid targets involved remain uncertain to this day.


Adapted from: Moffat J, Vincent F, Lee J, et al. Opportunities and challenges in phenotypic drug discovery: An industry perspective. Nat Rev Drug Discov 2017; 16:531–43. DOI: 10.1038/nrd.2017.111