Octanol–water partition coefficient measurements for the SAMPL6 blind prediction challenge

Abstract

Partition coefficients describe the equilibrium partitioning of a single, defined charge state of a solute between two liquid phases in contact, typically a neutral solute. Octanol–water partition coefficients ( $$K_{\\rm ow}$$ K ow ), or their logarithms (log\xa0 P ), are frequently used as a measure of lipophilicity in drug discovery. The partition coefficient is a physicochemical property that captures the thermodynamics of relative solvation between aqueous and nonpolar phases, and therefore provides an excellent test for physics-based computational models that predict properties of pharmaceutical relevance such as protein-ligand binding affinities or hydration/solvation free energies. The SAMPL6 Part II octanol–water partition coefficient prediction challenge used a subset of kinase inhibitor fragment-like compounds from the SAMPL6 $$\\hbox {p}{K}_{{\\rm a}}$$ p K a prediction challenge in a blind experimental benchmark. Following experimental data collection, the partition coefficient dataset was kept blinded until all predictions were collected from participating computational chemistry groups. A total of 91 submissions were received from 27 participating research groups. This paper presents the octanol–water log\xa0 P dataset for this SAMPL6 Part II partition coefficient challenge, which consisted of 11 compounds (six 4-aminoquinazolines, two benzimidazole, one pyrazolo[3,4-d]pyrimidine, one pyridine, one 2-oxoquinoline substructure containing compounds) with log\xa0 P values in the range of 1.95–4.09. We describe the potentiometric log\xa0 P measurement protocol used to collect this dataset using a Sirius T3, discuss the limitations of this experimental approach, and share suggestions for future log\xa0 P data collection efforts for the evaluation of computational methods.