Chemical target validation

Wyatt PG, Gilbert IH, Read KD et al (2011) Target validation linking target and chemical properties to desired product profile. Curr Topics Med Chem 11 1275-1283... 

Figure 3.3 The knowledge roadmap for target validation, beginning with a chemical effect between a small molecule and a protein target and ending with a beneficial clinical effect on a person with a disease.

The downside to the three-hybrid as a target validation tool is that a suitable attachment point must be found on the query molecule. Oftentimes, selection of an appropriate site requires structure-activity relationship (SAR) studies to avoid damaging the compound s binding affinity. Moreover, each chemical entity requires individual synthetic effort because the properties of... 

This example reinforces the critical importance of reliable target validation for a given disease. It seems likely that other kinases yet to emerge could impact chronic diseases but not suffer from such unforeseen target/disease related problems. If these are not tyrosine kinases, it may be easier to obtain selective inhibitors to avoid off-target effects while remaining in drug-like chemical space. While research continues into tyrosine kinases for chronic... 

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