The type of target influence the type of drug Main drugs’ categories –Small molecules –Biologicals (e.g. antibodies, hormones, etc) The drug discovery process for the two categories of drugs is not exactly the same In the rest of the presentation we will mainly focus on that for small molecules Target selection

General criteria for target choice Druggability: likelihood of being able to modulate a target with a drug Target selection

Druggability of small molecules targets polysaccharides lipids nucleic acids proteins Problems with toxicity, specificity, and difficulty in creating adequate ligands narrow mainly to protein the druggable targets Target selection X X X

Druggability Only 10% of the human genome represents druggable targets, and only half of those are relevant to disease. Target selection

The genome project and the“omics” era Target identification

The suffix -ome- as used in biology refers to a totality of some sort Genetic code Geneticcode Genome Trascriptome Proteome Metabolome Pathways static dynamic DNA RNA Proteins Complexity Target identification

Transcriptome: gene expression profiling However, it should be kept in mind that does not exist a complete match between the trascriptome and the proteome. Only a part of the genome is expressed in any given moment in both physiological and pathological conditions. Identification of difference in expression profile between physiological and pathological states could lead to the identification of new targets. Target identification

Techiniques to measure simoultaneously expression of multiple genes Differential display Subtractive cDNA library S.A.G.E Serial analysis of gene expression Microarray Target identification

Gene microarray Expression level of genes could be measured simoultaneously 1,28cm GeneChip Probe Array 18µm Target gene is present in thousands of copies * * * * * Hybridized Cell Target identification

Gene microarray applied to target discovery (Costingan et al., BMC Neuroscience 2002) Target identification

Gene microarray applied to target discovery Target identification

Ingenuity’s Network Target identification CV L5 Rx vs. Lx fold changes on top CGW L5 Rx vs. Lx fold changes on bottom

Proteomics Allow to identify difference in protein expression under different physiological and pathological conditions It is possible the identification of post-translation modifications (e.g. phosphorylation and glycosilation) It is more time consuming and require more sophisticated instruments than gene expression profiling. Target identification

2D-gel analysis pIpI MW Proteomics Target identification

Preoteomics applied to target identification Target identification