Evolution of Novartis' Small Molecule Screening Deck Design.

Area of Science:

• Drug Discovery
• Medicinal Chemistry
• Chemical Biology

Background:

• Historically, screening decks comprised all available compounds.
• The first NIBR screening deck (2015) utilized a 2D grid for diverse, property-optimized compound subsets.
• Learnings from the 2015 deck informed the design of subsequent generations.

Purpose of the Study:

• To summarize the evolution of screening deck design at NIBR.
• To detail the transition from property-based ranking to solubility and permeability criteria.
• To incorporate experimental assay data and biological activity profiles into deck design.

Main Methods:

• Development of a 2015 screening deck with property-based ranking and structural redundancy.
• Analysis of hit rates using traditional leadlikeness criteria (MW, clogP).
• Design of a 2019 screening deck prioritizing solubility and permeability, incorporating assay data and biological activity profiles.

Main Results:

• Traditional leadlikeness criteria (MW, clogP) were found to reduce hit rates for promising chemical starting points.
• The 2019 screening deck demonstrated improved compound selection based on solubility and permeability.
• Integration of experimental assay data and inferred biological activity enhanced compound set redundancy and diversity.

Conclusions:

• Screening deck design has evolved at NIBR to optimize compound selection for drug discovery.
• Prioritizing solubility and permeability over traditional leadlikeness criteria improves hit rates.
• Utilizing experimental data and biological profiles leads to more effective screening libraries.