Chromatographic Determination of Permeability-Relevant Lipophilicity Facilitates Rapid Analysis of Macrocyclic Peptide Scaffolds
Year: 2024
Type: article
Abstract: Hydrocarbon-determined shake-flask measurements have demonstrated great utility for optimizing lipophilicity during early drug discovery. Alternatively, chromatographic methods confer reduced experimental error and improved handling of complex mixtures. In this study, we developed a chromatographic approach for estimating hydrocarbon-water shake-flask partition coefficients for a variety of macrocyclic peptides and other bRo5 molecules including PROTACs. The model accurately predicts experimental shake-flask measurements with high reproducibility across a wide range of lipophilicities. The chromatographic retention times revealed subtle conformational effects and correlated with the ability to sequester hydrogen bond donors in low dielectric media. Estimations of shake-flask lipophilicity from our model also accurately predicted trends in MDCK passive cell permeability for a variety of thioether-cyclized decapeptides. This method provides a convenient, high-throughput approach for measuring lipophilic permeability efficiency and predicting passive cell permeability in bRo5 compounds that is suitable for multiplexing pure compounds or investigating the properties of complex library mixtures.
Source: Journal of Medicinal Chemistry
Authors: Grant Koch, Alexander Engstrom, Jaru Taechalertpaisarn, Justin Faris, Satoshi Ono, Matthew R. Naylor, R. Scott Lokey
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Award: G2468260890
OpenAlex ID: W4403760052