Target validation, drug discovery

Strachan, R.T., Ferrara, G. and Roth, B.L. (2006) Screening the receptorome an efficient approach for drug discovery and target validation. Drug Discovery Today, 11, 708-716. 

However, the target validation step is unique to target-based drug discovery. 

Epigenetic Targets in Drug Discovery Cell-Based Assays for HDAC Inhibitor Hit Validation... 

How to determine which protein activity should be targeted for drug discovery. For proteins with a clearly defined enzymatic activity, the use of catalytically inactive mutants has been proven to be useful. In the field of protein kinase research, kinase-dead mutants frequently behave as dominant-negatives, thus highlighting the importance of the kinase activity. In addition, the Shokat lab has developed a method allowing validation of the specific contribution of a kinase activity in cellular pathways. 

This raises the key test of target validation. Does a compound that has the appropriate potency, selectivity, and ADME properties, that is active in "predictive" animal models, and is free of other systems toxicology work in the targeted human disease state This is the ultimate test of a target-based drug discovery program. With the considerable compound attrition rates in moving from animals to diseased humans, this has not proven to be a predictable transition. A case in point is that of the NKl receptor activated by the peptide, substance P. 

Since one of the fundamental requirements for crystallization is good solution properties, this type of screen can also be used to assess suitable solution conditions for crystallization trials. The application of the described workflow led to the successful expression and purification of several kinases, which are validated targets in drug discovery. Figure 15.2-5 shows a gallery of the corresponding spectra, which were recorded on the uniformly 15N-labeled proteins in our group. 

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