Towards holistic Compound Quality Scores: Extending ligand efficiency indices with compound pharmacokinetic characteristics

The suitability of small molecules as oral drugs is often assessed by simple physicochemical rules, the application of ligand efficiency scores or by composite scores based on physicochemical compound properties. These rules and scores are empirical and typically lack mechanistic background, such as information on pharmacokinetics (PK). We introduce new types of Compound Quality Scores (CQS, specifically called dose scores and c(max) scores), which explicitly include predicted or, when available, experimental PK parameters and combine these with on-target potency. These CQS scores are surrogates for an estimated dose and corresponding c(max) and allow prioritizing of compounds within test cascades as well as before synthesis. We demonstrate the complementarity and, in most cases, superior performance relative to existing efficiency metrics by project examples.

Automated summary

The suitability of small molecules as oral drugs is often assessed by simple physicochemical rules or scores, which lack mechanistic background. This paper introduces new Compound Quality Scores that incorporate pharmacokinetic parameters and on-target potency, demonstrating their complementarity and superior performance through project examples.