Application of Mechanistic Multiparameter Optimization and Large-Scale In Vitro to In Vivo Pharmacokinetics Correlations to Small-Molecule Therapeutic Projects

Computational chemistry and machine learning are used in drug discovery to predict the target-specific and pharmacokinetic properties of molecules. Multiparameter optimization (MPO) functions are used to summarize multiple properties into a single score, aiding compound prioritization. However, over-reliance on subjective MPO functions risks reinforcing human bias. Mechanistic modeling approaches based on physiological relevance can be adapted to meet different potential key objectives of the project (e.g., minimizing dose, maximizing safety margins, and/or minimizing drug–drug interaction risk) while retaining the same underlying model structure. The current work incorporates recent approaches to predict in vivo pharmacokinetic (PK) properties and validates in vitro to in vivo correlation analysis to support mechanistic PK MPO. Examples of use and impact in small-molecule drug discovery projects are provided. Overall, the mechanistic MPO identifies 83% of the compounds considered as short-listed for clinical experiments in the top second percentile, and 100% in the top 10th percentile, resulting in an area under the receiver operating characteristic curve (AUCROC) > 0.95. In addition, the MPO score successfully recapitulates the chronological progression of the optimization process across different scaffolds. Finally, the MPO scores for compounds characterized in pharmacokinetics experiments are markedly higher compared with the rest of the compounds being synthesized, highlighting the potential of this tool to reduce the reliance on in vivo testing for compound screening.