Relationship between Passive Permeability and Molecular Polarity Using Block Relevance Analysis.

Abstract

EPSA is an experimental descriptor of molecular polarity obtained from chromatographic retention in supercritical fluid chromatography (SFC) systems, previously shown by Goetz et al. to correlate with passive permeability of cyclic peptides. The present study focuses on EPSA in relation to passive permeability of small molecules. We applied block relevance (BR) analysis to interpret the relative significance of mechanistic forces prevailing in EPSA. The BR analysis is a computational tool that allows the interpretation of the balance of intermolecular interactions governing systems such as the aforementioned chromatographic retention in EPSA. EPSA and passive permeability determined by Ralph Russ canine kidney cells (RRCK) or low efflux Madin Darby canine kidney cells (MDCK-LE) and human epithelial colorectal adenocarcinoma cells (Caco-2), studied on a data set of commercial drugs, indicated that EPSA is relevant in describing permeability of hydrophilic drugs (CLogP < 1). We then verified, on a data set of 1699 Rule of 5 compliant Pfizer compounds, that when CLogP < 1, a value of EPSA < 100 significantly increases the likelihood of high permeability.