June 5, 2005, ASMS 2005, San Antonio, TX, USA

Automated LC/MS Purity Analysis of a Compound Screening Collection

Robyn Rourick

Abstract

The goal of drug discovery is the generation of novel lead candidates with suitable pharmaceutical properties for preclinical evaluation. This process is initiated by the identification of a target followed by high throughput screening activities in efforts to identify active chemotypes from extensive compound collections. Many in-house collections contain compounds which were synthesized several years prior or obtained from outside resources. Since screening hits serve as the starting point for synthetic optimization, it is imperative that the expected composition of each hit be confirmed. If unchecked, inaccurate structures, impurities and degradants lead to confusion in the SAR for the drug discovery team. LC/MS analysis approaches including UV and ELSD detection have become the industry standard for confirming the integrity of a compound which has demonstrated activity in a biological screen. Typical workflows require the re-plating of hits by Compound Management groups followed by a transfer of plates to an Analytical function for LC/MS analysis. Upon completion of data analysis, results are then transferred to an Informatics group to appropriately archive and provide access to the originating project team.

In efforts to facilitate confirmation and speed up the Discovery process, a 5-channel MUX LCT Premier has been integrated with our Hit-Picker technology. This allows us to directly analyze any component or portion of our compound collection by directly sampling from a 1mM DMSO stock solution archived on the platform. The parallel nature of the technology allows the collection of high resolution mass spectra on all components of a complex mixture. To handle the continuous stream of higher volume data, we have implemented a data analysis scheme which leverages Advanced Chemistry Development's (ACD/Labs) Automation Server. This package allows us to generate results on-the-fly by routinely accessing raw results from the acquisition computer's hard-drive. Additionally, the ACD tools enable the rigorous assessment of the LC/MS data so that minimal expert review is needed prior to the release of the finalized results. The current purity analysis workflow enabled by our proprietary hardware integration will be discussed.

Download the presentation in Adobe Acrobat format (1.57 Mb PDF file).

Relevant Products: ACD/Automation Server, ACD/MS Manager, ACD/ChromManager, ACD/ChemBasic, ACD/SpecManager

Relevant Solutions: Combinatorial and High-Throughput Chemists, Analytical Laboratory, Chemical Databasing