Target Discovery and Validation Reviews and Protocols

10 Sioud
Fig. 2. Schematic of target and drug discovery steps.
through high-throughput screening (Fig. 2). This process requires the use of robust
assay of target activity and a good collection of component libraries for testing.
Positive “hits” from the primary screening usually are evaluated on the basis of
efficacy, specificity, toxicity, and pharmacology in animal models, to identify lead
compounds for further optimization. Primary screening for efficacy and specificity
can be performed in cell systems. However, active agents in vitro may be inactive
in vivo because of in vivo metabolism, elimination, and poor penetration into targets
tissues or just because the target was not involved in the pathway under investigation
in vivo. During preclinical animal studies (e.g., pharmacology and
toxicity), it is important to use biomarkers that can be translated for human use in
phase 1 studies. Additionally, it is urgent to use appropriate animal models and
experimental design. Indeed, many novel drugs that worked in animal models have
failed in humans. Drugs failed because of lack of efficacy.
Given the huge number of potential druggable targets offered by the human
genome sequence and new technologies for target validation such as RNAi, new
smart drugs for most complex diseases may be developed in the near future. To
reach this goal, pharmaceutical companies should examine thoroughly the
validity of the target at early stage and define rational drug discovery programs.
It does not matter how many targets we select: what really matters is whether
the selected targets are involved in the disease under study.