title: A novel method for high throughput lipophilicity determination by microscale shake flask and liquid chromatography tandem mass spectrometry.
abstract: Modern small molecule drug design requires the optimization of not only the binding characteristics of the molecule but also its physicochemical properties for ADMET performance. A key physical property is lipophilicity and medicinal chemists need rapid access to high quality data in order to drive their decision making. Traditionally lipophilicity (log D) measurements are performed with a shake flask method and UV determination. This method suffers from low sensitivity and is not easily converted to a high throughput format. Over the past decade, several groups have taken different approaches to improve this assay, including replacing the shake flask method with one that utilizes reverse phase HPLC. Here we describe a new microscale shake flask method that utilizes UPLC-MS/MS to achieve increased throughput, sensitivity and accuracy. Approaches for assessing data quality are also described. This platform technology only requires micrograms of compound and is routinely used by most small molecule drug discovery project teams at Genentech.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080-4990, USA. lin.baiwei@gene.com.
authors.forename: Baiwei
authors.initials: B
authors.lastname: Lin
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Pease
mesh_terms: D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D056148:Chromatography, Reverse-Phase / Q000379:methods*; D057166:High-Throughput Screening Assays; D008055:Lipids / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D008055:Lipids