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

Area of Science:

• Pharmacology and Drug Discovery
• Biomolecular Screening

Background:

• Pharmaceutical innovation in new molecular entities has lagged.
• Early 2000s FDA approvals show phenotypic lead generation yielded more first-in-class drugs than molecularly targeted strategies.
• Challenges in target validation have diminished the impact of genomics in drug discovery.

Purpose of the Study:

• To introduce and overview special issues on Phenotypic Drug Discovery (PDD).
• To define PDD terminology and establish its business case.
• To discuss key PDD issues, challenges, and potential solutions.

Main Methods:

• Review of historical drug approval data (1999-2008) comparing phenotypic and target-based strategies.
• Discussion of organizational and implementation challenges in PDD.
• Exploration of a 'neoclassic' PDD vision integrating phenotypic, functional, and genomics-era technologies.

Main Results:

• Phenotypic strategies were more successful in identifying first-in-class small-molecule drugs compared to target-based approaches during the specified period.
• A growing trend in pharmaceutical companies is reconsidering PDD.
• Key issues in PDD include assay performance, chemical optimization, and target identification.

Conclusions:

• Phenotypic drug discovery (PDD) is re-emerging as a viable and effective strategy in pharmaceutical research.
• Addressing challenges in PDD implementation is crucial for its success.
• A hybrid approach combining PDD with modern technological innovations offers a promising future for drug discovery.