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Chemical genomics in yeast

Many drugs have unknown, controversial or multiple mechanisms of action. Four recent ‘chemical genomic’ studies, using genome-scale collections of yeast gene deletions that were either arrayed or barcoded, have presented complementary approaches to identifying gene-drug and pathwaydrug interactions. deposited research The fact that much of modern drug research is target-oriented obscures the long history during which the effects of drugs were discovered prior to identification of their targets. There remain many. | Minireview Chemical genomics in yeast Charles Brenner Address Departments of Genetics and Biochemistry and the Norris Cotton Cancer Center Dartmouth Medical School Lebanon NH 03756 USA. E-mail charles.brenner@dartmouth.edu Published 27 August 2004 Genome Biology 2004 5 240 The electronic version of this article is the complete one and can be found online at http genomebiology.com 2004 5 9 240 2004 BioMed Central Ltd Abstract Many drugs have unknown controversial or multiple mechanisms of action. Four recent chemical genomic studies using genome-scale collections of yeast gene deletions that were either arrayed or barcoded have presented complementary approaches to identifying gene-drug and pathwaydrug interactions. The fact that much of modern drug research is target-oriented obscures the long history during which the effects of drugs were discovered prior to identification of their targets. There remain many natural products and drugs for which the cellular target protein s are yet to be fully characterized. Without the identification of specific targets it is extremely difficult to modify and improve the performance of drugs and to determine whether side effects are due to effects on the primary target or off target effects. Indeed mouse-on-the-hotplate analgesia assays 1 seem crude in this era of high-throughput screening and structure-based refinement of for example inhibitors of cyclooxygenase 2 COX-2 2 . But the advantage of targetless whole-animal assays is that compounds that would pass some early stage of in vitro screening only later to fail to have in vivo efficacy do not score positively in whole-animal assays. This is important because acceleration of failure is considered to be a cost- and time-conserving necessity in drug discovery. There is clearly a need to work through the legacy compound collections owned by pharmaceutical companies. In addition the introduction of zebrafish 3 and invertebrate 4 systems into drug screening for the advantages .