'Proteome Mining' to isolate drug targets

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Related tags: Drug discovery

Researchers have claimed proteome mining could make the discovery
and development of cancer, hypertension, diabetes, inflammation and
infectious disease drugs enormously more effective, fast tracking
protein targets that can be tested against compound libraries.

Proteome mining involves isolating the hundreds of enzymes that control key cellular processes and performing mass screening for potential drugs to affect those switches. From this screening, which is relatively quick and inexpensive, new drugs to treat disease can be rapidly identified and progressed to animal testing.

Tim Haystead, pharmacologist at Duke University told DrugResearcher.com​: "One of the greatest strengths of the technology is its ability to identify off target liabilities of both existing drugs as well as developing drugs. For these reasons it can be applied at every level of the drug discovery process. Lead molecules are not only identified but also enable the affinity of the molecule for all targets to be measured."

Haystead, used proteome mining to identify new antimalarial drugs without the eye-damaging effects of current drugs such as chloroquine (Aralen. Researchers isolated from proteomes of human cells those proteins that interact with antimalarial drugs. This screen revealed the drugs effects on a particular enzyme called aldehyde dehydrogenase appear to be central to the side effect.

However, another target of chloroquine, a human enzyme called quinone reductase 2 appeared to play a role in antimalarial action. This enzyme appears to be part of a mechanism to protect red blood cells against stress.

"We believe the drug inhibits the human enzyme, which the malaria parasite is essentially using to protect itself inside the blood cell," said Haystead. "And we believe if you inhibit the enzyme then the parasite can't survive, so drugs that target it will confer resistance to malaria."

The approach used enables mining of large combinatorial chemical libraries containing drug-like molecules for novel target associations. These can become the starting points for improved selectivity, depending on the protein targets.

Haystead added: "In addition, to producing antimalarials that exploit redox analogs, proteome mining technology can be used to identify multiple antimalarial targets at all stages of the parasite life cycle. This includes both additional host targets in the liver and blood as well as parasite proteins. Given sufficient resources the technology could be applied to completely eradicate the disease and drive it to extinction."

Regarding the future of proteome mining, Haystead was confident that all drugs will be discovered and developed using this technology.

Combining data-mining techniques with high-precision screening and library selection can offer dramatic improvements in productivity.

In collaboration with Pfizer​, Tripos has developed the SARNavigator suite of tools for analysing high-throughput screening results. The package allows researchers to examine structure-activity relations (SAR) quantitatively to help determine which hits should go forward into the lead identification and optimization phase.

Applying informatics along the discovery process can reduce the time taken in each phase, both by exploiting mining to reduce the attrition of candidate compounds and by managing the logistics of the whole process. Tripos and Pfizer have found the time taken from initial screening to a preclinical drug candidate can be reduced to 9-18 months from an industry standard of 2½-3 years.

Drug-discovery company Amphora​, at Research Triangle Park, North Carolina, focuses on finding small-molecule therapeutics for big-pharma partners such as Aventis. Structure-activity relation modelling allows the firm's chemists to move directly from primary screening to medicinal chemistry stage. "This enables the process to go from target to lead in just six months.

Related topics: Ingredients

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