Scrreening in Drug Discovery

Screening in drug discovery is conducted in a streamline assay format aimed at hit identification. Screening may be low throughput (10 000–50 000 assay points), medium throughput (50 000–100 000 data points) or high throughput (100 000–500 000+ data points). Ideal screening procedure should be cost-effective and robust under varying conditions such as chemical types. Two well-established strategies, diversity-based and focused screening, have been compared and reviewed. Focused screening is more widely used and the most popular of these methods involves the use of 3D information on targets where crystal structure is available. Diversity screening means testing all the molecules that could be considered drug candidates and the number could go up to one million samples. This approach is based on a commitment to increase in capacity by automation, miniaturisation and throughput with reduction of cost.
1. Cell-based Screening System
Unlike traditional methods in the drug discovery process, the cell-based method provides deep biological information (time, space and activity) about a drug candidate’s physiological impact on specific cellular targets within living cells. This approach provides significant insight into the potential efficacy and toxicity of a drug candidate on cells before initiating animal testing and human clinical trials, thereby saving substantial time and expense.
Cell-based assays have the advantage that they can be miniaturised to increase screening throughput and reduce costs. Functional cell-based assays would be useful for screening of modulators of ion channels.
Because the binding sites may be unknown, formatting of these assays is difficult with the use of traditional biochemical or ligand-displacementmethods. New optical assays employ fluorescent or optical readouts andpermit cell-based assays for most targets, including ion channels. Further, genetically encoded probes offer the possibility of biosensors for intracellular biochemistry, specifically localised targets and protein–protein interactions.
2. Receptor Targets: Human versus Animal Tissues

In the traditional approach to drug discovery, compounds are screened against animal tissues containing many different types of receptors.
Companies such as Lundbeck Research USA follow approaches involving use of human tissues. The advantages of using human tissues are:
1. By having an isolated receptor as a target, chemists are better able to design compounds that interact with only the target of interest and not with other receptors that may be responsible for
side-effects.

2. Using human receptors as drug design targets will substantially reduce the number of problems that often arise during the drug development process as a result of differences in a compound’s activity in humans compared with its activity in animal models.
3. Use of human tissues may be more cost-effective than traditional drug discovery because one can eliminate or redesign compounds that react poorly with human receptor targets prior to initiating the costly activities related to preclinical testing and clinical trials.
4. A compound targeted against specific receptor in human tissues is better validated for entry into clinical development.
3. Tissue Screening
Testing directly in human tissue rather than in animal models or yeast allows drug development teams to obtain vital information about what their gene of interest is doing in a human system. Because animal models are often not predictive of how drugs will behave in humans, obtaining
information directly from human tissues is a critical step in choosing one target from many candidates. Even after the drug development process has begun, determining where a particular gene is expressed in other, perhaps unexpected, sites within the body may assist researchers in the design and interpretation of preclinical or clinical studies.