Predicting Octanol–Water Partition Coefficients of Fluorinated Drug-Like Molecules: A Combined Experimental and Theoretical Study

Abstract

In this paper, a dataset of 11 fluorinated compounds containing a variety of functional groups (amides, esters, indoles, and ethers) as well as mono, gem-difluoro, erythro-difluoro, and threo-difluoro patterns were synthesised and their octanol–water partition coefficients (log P) were measured using a shake-flask method. The resulting data was used to assess the performance of several popular empirical fragment-based methods as well as quantum chemical implicit solvent models (SMD and SM12). Overall, the empirical miLOGP, ALOGPS, and ALOGP methods performed the best with a mean absolute deviation (MAD) of ~0.25 log units, while the best performing implicit solvent model SMD has a slightly higher MAD of 0.36 log units. Based on the present work and previous studies, the miLOGP and ALOGP empirical methods are recommended for fast and moderately accurate prediction of log P for neutral organic solutes.