Mass screening compound libraries

Hindsgaul, O. Schriemer, D.C. Methods Using Frontal Chromatography-Mass Spectrometry for Screening Compound Libraries, PCT Int. Appl. (1999), 90 pp., WO 9950669 Al 19991007. 

Xu, R. et al. 2002. Application of parallel liquid chromatography/mass spectrometry for high throughput microsomal stability screening of compound libraries. J. Am. Soc. Mass Spectrom. 13 155. 

L., Hindsgaul, O. Micro-scale frontal affinity chromatography with mass spectrometric detection A new method for the screening of compound libraries. Angew Chem Int Ed 1998, 37, 3383-3387. 

For those readers who are not yet familiar with mass spectrometry, the introduction provides an explanation of the basics of mass spectrometry and its instrumentation as well as practical aspects and applications in bioanalysis. Next, a block of three chapters shows different affinity selection procedures suitable to identify hits from combinatorial compound libraries. This subject, being metaphorically speaking a search for a needle in a haystack, is of outstanding relevance for big pharma . The techniques described here offer real high throughput capabilities and are implemented already in the routine industrial screening... 

Wang, T. Cohen, J. Kassel, D. B. Zeng, L. 1999. A multiple electrospray interface for parallel mass spectrometric analyses of compound libraries. Comb. Chem. High Throughput Screen, 2,327-334. 

Llorens, O., Perez, J.J., and Villar, H.O., Toward the design of chemical libraries for mass screening biased against mutagenic compounds, J. Med. Chem., 44, 2793-2804, 2001. 

After first verifying that bead-bound monomers had minimal affinity for target RNA 12, the entire 11,325-compound library was screened with fluorescently-labeled HIV-1 FSS RNA as a pool. Fluorescent beads were then removed, cleaved, and cleaved material analyzed. As the stoichiometry of the library screen was set up such that bead-bound monomers were in excess (a choice made so as to favor dimmer formation on bead rather than in solution), mass spectrometry revealed only the identity of component monomers rather than the full structure of selected compounds. Nevertheless, this provided a substantial simplification of the library in a single step three monomers were identified as being selected in replicate experiments, potentially representing six unique compounds, or 0.05% of the library (ignoring terminus differentiation due to resin attachment taking this into consideration raises the number of compounds to a still-low 9). 

Schriemer, D.C. Bundle, D.R. Li, L. Hindsgaul, O. Micro-Scale Frontal Affinity Chromatography with Mass Spectrometric Detection A New Method for the Screening of Compound Libraries, Angew. Chem., Int. Ed. 37, 3383-3387 (1998). 

Another successful approach to improve the quahty of libraries prior to screening has been mass-triggered fractionation. This approach uses MS-triggered LC fraction collection for sample purihcation and was hrst introduced by Kassel et al. [47,48], who demonstrated the purihcation of a 192 compound library to a purity sufficient for biological correlation (80-90% purity) in a 24-hour period. Mass-triggered fractionation has seen broad apphcation in the purihcation of combinatorial libraries [49,50] as well as natural product samples [51]. Several commercial systems now provide this capability [52,53]. Mass-triggered fractionation has also been adapted to supercrihcal huid chromatography (SEC) formats for the purihcation of compound libraries and natural product extracts [54-58]. 

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