In the process of preclinical testing of a compound or biological agent into a drug, the compound involved must go through the testing phase. First, we need to identify potential targets that can treat the disease. Then, a variety of compounds or preparations are screened out. Any compound that has shown potential as a drug for the treatment of this disease needs to be tested for toxicity before clinical testing to reduce the possibility of injury.
What is the basis of preclinical testing?
According to US Food and Drug Administration (FDA) regulations, a series of tests are required before a new drug is approved for use. In the first stage, basic research determines a hypothetical target for the treatment of a certain disease, and then screens small molecules or biological compounds to discover any substance with the potential to treat the disease.
Then, a preclinical research phase followed, before which, as described above, the potential toxicity of the compound was determined. Factors such as dosage, method of administration, and frequency of administration are also studied to support the next phase of clinical trials, also known as clinical studies. Here, the compound was tested in humans to see if it can be used to treat the disease that triggered the search.
Identify potential targets
The main reason why the compound cannot be used as a medicine is that the compound cannot be used as a medicine or is toxic. Therefore, determining drug targets is one of the most important parts of preclinical testing. The latest advances in technology have increased the number of potential targets or targets that can be used. Bioinformatics tools can now be used to “mine” the available data to search for these potential targets. These may come from published studies or patents, gene expression and proteomics data sets, data on transgenic phenotypes, and compound analysis data.
Targets include a wide range of biomolecules, such as proteins, RNA and DNA. A key requirement for treating biomolecules as targets is whether they are “absorbable by the body.” This means that the compound to be tested needs to be able to approach the target and then induce a measurable response.
Certain classes of target compounds are more suitable for different classes of compounds. For example, G protein-coupled receptors are good potential targets for small molecules, and antibodies are more suitable for blocking protein-protein interactions.
How to find the “target”?
Once the treatment goal is determined, the next stage of preclinical testing will be to determine the “hit drug.” The effects of these compounds may be able to treat the disease. Here, different kinds of measurements need to be used.
In high-throughput screening, a large number of compounds are tested against target compounds to see if any compounds show the potential to enter the next stage. These rely on automated systems that can test a large number of compounds without making any assumptions about how these compounds might interact with the target. In contrast, centralized screening can only detect a smaller number of compounds, but compounds that are more likely to interact with the target. Other screening methods used in this stage of preclinical testing include: fragment screening (in which the protein structure of the compound-target interaction is determined) and physiological screening (in which only tissues are used instead of targets or cells).
What happens once the hit is confirmed?
Once the target is determined, it will be further studied to make the compound more selective and effective. This stage of preclinical testing studies the structure-activity relationship between the compound and the target, and then studies whether the compound interacts with the target of different species.
This indicates whether the compound can be tested in animal models of the disease, which is an important part of toxicity testing during preclinical testing. The compound is then refined to maintain the beneficial properties while reducing or eliminating the unfavorable aspects.
What other factors need to be considered for pre-clinical testing?
Other factors that should be considered during preclinical testing are the nature of the disease and the demographic characteristics of the patient suffering from it.
For example, neurodegenerative diseases (such as Alzheimer’s disease) are progressive diseases and therefore require long-term treatment. This means that in preclinical testing, it is crucial to test the compound in a way that mimics long-term treatment. This highlights any compounds that may cause toxicity after prolonged exposure.
Because neurodegenerative diseases have a greater impact on the elderly, potential reproductive toxicity can be investigated in the later stages of preclinical testing. However, since these patients may also be taking other drugs, it may be prudent to test the interaction between the compound and the approved drug as early as possible in preclinical testing.
The route and frequency of administration are also factors that need to be considered in patient demographics. For example, in neurodegenerative diseases, patients will benefit from more manageable treatments, such as small tablets or liquids taken once a day or less. Focusing on compounds that can be administered in this way may become the focus of preclinical testing.
1.fda.gov The Drug Development Process www.fda.gov/…/drug-development-process
2. Hughes, J. P., et al. (2011) Principles of early drug discovery. British Journal of Pharmacology doi: 10.1111/j.1476-5381.2010.01127.x
3. Steinmetz, K. L. and Spack, E. G. (2009) The basics of preclinical drug development for neurodegenerative disease indications. BMC Neurology https://doi.org/10.1186/1471-2377-9-S1-S2