Octanol-water partition coefficient measurements for the SAMPL6 Blind Prediction Challenge

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 ow), or their logarithms (log 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 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 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 P values in the range of 1.95–4.09. We describe the potentiometric log 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 P data collection efforts for the evaluation of computational methods. * SAMPL : Statistical Assessment of the Modeling of Proteins and Ligands log P : log10 of the organic solvent-water partition coefficient ( Kow , refers to partition of neutral species unless stated otherwise) log D : log10 of organic solvent-water distribution coefficient ( Dow ) log R : log10 of the volumetric ratios of partition solvents (octanol to water) p K a : −log10 of the acid dissociation equilibrium constant po K a : −log10 apparent acid dissociation equilibrium constant in octanol-water biphasic system ISA : Ionic-strength adjusted solution with 0.15 M KCl SEM : Standard error of the mean LC-MS : Liquid chromatography-mass spectrometry NMR : Nuclear magnetic resonance spectroscopy HRMS : High-resolution mass spectrometry octanol : 1-octanol, also known as n-octanol