Speeding Drug Development

The landscape in pharmaceutical drug discovery has changed considerably in the last few years. The huge promise of combinatorial chemistry has faded due to the unexpected low success rates for these randomly designed compounds. Now drug companies are focusing on smaller and more targeted drug libraries. Still the need for high throughput has not abated as there is a strong desire to run more and more tests on these compounds earlier in the lead generation process. Naturally the first criterion for a successful drug is biological activity, and high-throughput screens do exist to meet the speed requirements. However, drugs fail for many reasons having to do with their life cycle in the body. These pharmacokinetic properties are often referred to by these specific steps, which include adsorption, distribution, metabolism, and elimination (ADME).

Drug Discovery/Development Process Highlighted text shows where Syagen’s high-throughput molecular analyzer can enhance the discovery process. The arrow denotes later stage testing that can be conducted on compound libraries in order to "weed out" poor candidates early.

Proteomics – The Link between Genomics and Drug Discovery

The goal of drug discovery is to find new molecules that bind with specific proteins in a manner that changes their function for the benefit of life. Studying the entire complement of proteins expressed by a particular cell, organism or tissue at a given time and under a specific set of environmental conditions will require developing new automated and high-speed methods for analyzing the protein content of cell lines. These diagnostics will help make possible an understanding of whole system biological function for improved drug therapy and early detection of disease, such as cancer. A recent National Academy of Sciences symposium “Defining the Mandate of Proteomics in the Post-Genomic Era” highlighting the daunting tasks ahead clearly articulate that instrumentation that achieves high-throughput and high dynamic range is needed.

High-throughput molecular screening

Syagen has developed two key technologies that enable significantly increased analysis rates relative to existing technology.

• Photoionization mass spectrometry (PI MS) offers detection of a wide range of compounds including those that are not polar enough to be seen with APCI and ESI, with less susceptibility to ion suppression. Syagen has developed PhotoMate APPI sources, which are now available on most major LC/MS instruments. Syagen also has developed a low-pressure PI (LPPI) source that it has integrated to its Radiance Pro^® high-throughput molecular analyzer. The LPPI source further reduces ion suppression relative to API sources and enables analyses of compound mixtures without the need for chromatography in many cases. The Radiance Pro offers the best combination of both accurate and high-speed analysis compared to existing methods of high-throughput characterization.
  
  
• Quadrupole ion trap, time-of-flight (QitTof™) MS is a means to conduct MS/MS analyses at high repetition rates. This capability is very important when combining structure analyses with high-speed chromatography. A particularly important application is the sequencing of peptides from protein digest mixtures. The enormously large number of proteins in a single cell line coupled with the little understanding of their identification and function begs for instrumentation that can provide high-speed analyses. One means to achieve this is to separate a protein mixture by ion exchange and/or liquid chromatography and digest each of the protein fractions to give a peptide mixture. The protein digest mixtures are further separated chromatographically and then analyzed by MALDI or ESI MS. The latter method permits on-line analysis, however, in order to increase throughput, it is highly advantageous to operate at fast separation rates using capillary LC or CE. This puts great demands on the MS system to conduct MS/MS peptide sequencing fast enough to fully resolve the narrow chromatographic peaks, particularly for co-eluting peptides. The QitTof MS is capable of doing MS/MS at up to 10x faster than conventional methods such as ion trap MS analysis.

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