Missing the target?



In his comment article, David Fox (Chemistry World, January 2012, p42) highlights the importance of having access to a well-curated repository of small molecules for drug discovery (and chemical genomics), but he feels that it is important to ’combine a well-validated target with a means of intervention that minimises attrition risks’. It is more arguable that it is precisely the target-based strategy of modern pharmacology that has got us into trouble. A return to physiological or phenotype-based screening would avoid the initial need for defined targets (plural) and provides an assessment of both toxicity and efficacy at a physiological level from the start. This systems view sits well with the increasing recognition of the importance of targeting networks in disease, the ’metabolite-likeness’ of effective drugs, the ’off-target’ effects of most successful drugs, the effectiveness of drug target combinations in modifying pathway behaviour, and the major importance of drug transporters in affecting drug distribution, efficacy and toxicity. Function first, target(s) second.

University of Manchester, UK