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Drug Discov Today. 2011 Sep;16(17-18):822-30. doi: 10.1016/j.drudis.2011.06.001. Epub 2011 Jun 16.

Getting physical in drug discovery II: the impact of chromatographic hydrophobicity measurements and aromaticity.

Author information

1
Department of CSC Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire, SG1 2NY, UK. Rob.J.Young@gsk.com

Abstract

Here, we review the performance of chromatographic hydrophobicity measurements in a data set of 100,000 GlaxoSmithKline compounds, demonstrating the advantages of the method over octanol-water partitioning and highlighting new insights for drug discovery. The value of chromatographic measurements, versus other hydrophobicity estimates, was supported by improved relationships with solubility, permeation, cytochrome P450s, intrinsic clearance, hERG binding and promiscuity. We also observed marked differentiation of the relative influence of intrinsic and effective hydrophobicity. The summing of hydrophobicity values plus aromatic ring count [logD(pH7.4) (or logP)+#Ar], indicated a wide relevance for simplistic 'property forecast indices' in developability assays, clearly enhanced by chromatographic values; therefore establishing new foundations for enriching property-based drug design.

PMID:
21704184
DOI:
10.1016/j.drudis.2011.06.001
[Indexed for MEDLINE]

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