Neoclassic drug discovery: the case for lead generation using phenotypic and functional approaches

J Biomol Screen. 2013 Dec;18(10):1143-55. doi: 10.1177/1087057113506118. Epub 2013 Sep 30.


Innovation and new molecular entity production by the pharmaceutical industry has been below expectations. Surprisingly, more first-in-class small-molecule drugs approved by the U.S. Food and Drug Administration (FDA) between 1999 and 2008 were identified by functional phenotypic lead generation strategies reminiscent of pre-genomics pharmacology than contemporary molecular targeted strategies that encompass the vast majority of lead generation efforts. This observation, in conjunction with the difficulty in validating molecular targets for drug discovery, has diminished the impact of the "genomics revolution" and has led to a growing grassroots movement and now broader trend in pharma to reconsider the use of modern physiology-based or phenotypic drug discovery (PDD) strategies. This "From the Guest Editors" column provides an introduction and overview of the two-part special issues of Journal of Biomolecular Screening on PDD. Terminology and the business case for use of PDD are defined. Key issues such as assay performance, chemical optimization, target identification, and challenges to the organization and implementation of PDD are discussed. Possible solutions for these challenges and a new neoclassic vision for PDD that combines phenotypic and functional approaches with technology innovations resulting from the genomics-driven era of target-based drug discovery (TDD) are also described. Finally, an overview of the manuscripts in this special edition is provided.

Keywords: PDD; TDD; cell-based assays; drug discovery; empirical drug discovery; functional screening; lead generation; phenotypic drug discovery.

Publication types

  • Review

MeSH terms

  • Animals
  • Biological Assay
  • Drug Discovery / methods*
  • Drug Industry
  • Genomics
  • Humans
  • Molecular Targeted Therapy
  • Phenotype