Target Selection and Validation

What is A Good Target?

Drug target is defined as the biological entity that interacts with and is regulated by a specific compound. This interaction is related to clinical effects and can be used for disease diagnostic and treatment.

In the history of diseases, there are a series of proteins or genes that cause disease that could be very interesting but are rarely good drug targets for small molecules. Many examples showed that exploring the complete pathogenesis of a disease is not mandatory for discovering drugs that relieve symptoms and counteract potentially fatal conditions. Receptors are proteins that are specialized in modulating cell functions. According to the statistics, more than 60% of targets are on the surface of cells and 44% of human targets are receptors. Among them, 42% are G protein-coupled receptors. Despite there being 20,000 genes in humans, the number of possible targets is often estimated to be only a few thousand.

Fig 1. Target identification can be split into target deconvolution and target discovery. (Van, 2015)

The Introduction and Necessity for Target Selection and Validation

In order to develop a real new drug, the most important task is to find a new target and then find a small molecule that specifically binds to the target. As the first step in drug discovery, target selection involves a wide range of techniques to demonstrate that the effect of the drug on the target is safe and effective. Early in-depth target selection and validation enables better understanding between target manipulation and disease efficacy so that increases the likelihood of clinical success.

There are three drug discovery strategies for small molecules, which include target-based screening strategy, phenotypic screening strategy, and fast-follower strategy. In general, target identification can be split into target deconvolution and target discovery. The target deconvolution is always used to identify the target against an active compound via phenotypic screening. Target discovery would be used to find a new target for medical use.

Techniques for Target Selection and Validation

There are various methods for target selection and validation based on fast-developing technologies, such as microscopy, automation, molecular biology, bioinformatics, etc. It should be noted that these technologies become obsolete very quickly and often require multiple technologies to be used in conjunction.

• Affinity Chromatography - The method to separate mixtures based on different affinities. Using an immobilized active small molecule, the best binding protein can be captured from the mixture.
• Genetic Methods - The powerful molecular biology tools allow modulation of gene expression for target deconvolution and target discovery. DNA microarrays or sequencing can also be used to identify existing modulations in disease-related gene expression.
• Haploinsufficiency Profiling in Yeast - Use at least one compound of interest and a set of strains to obtain a protein that directly or indirectly interacts with the compound by deleting one of the two genes in diploid yeast.
• Analysis of Resistant Mutants - This method is very useful in determining the targets derived from a phenotypic screen with bacteria or viruses. And the mutated gene often reveals the target of the antibiotic.
• siRNA for Target Validation - Using siRNA to mimic antagonistic drugs for gene expression suppression can test the potential of proteins as drug targets in the absence of drugs.
• Yeast Three-Hybrid System - Yeast cells are genetically engineered to send out signals when small molecules bind to target proteins.
• DNA Microarrays - On the DNA microarray, all genes whose expression is up-regulated or down-regulated in the disease can be obtained to find potential drug targets.
• Comparative Profiling - According to the basic idea, that is, compounds with roughly the same characteristics have roughly the same target so that the target of the compound can be predicted by referring to the compound library of the known target.
• Analysis of the Pathophysiology - A detailed analysis of pathophysiology can reveal new and interesting targets.
• The Study of Existing Drugs - Use the latest technology and theories to conduct in-depth research on old drugs to find new potential targets.
• Systems Biology - Study the dynamic interactions between all the components of a biological system to better understand and predict the behavior of an organism.

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Reference

1. Van den Broeck, W. M. Drug Targets, Target Identification, Validation, and Screening. The Practice of Medicinal Chemistry. Academic Press. 2015: 45-70.