Drug design is a costly and lengthy process. Researchers must deploy a complex combination of experimental models in order to identify effective therapeutic entities. Yet despite enormous technical advances in genomics and transcriptomics, attrition rates in drug development remain inordinately high; as much as 95% for novel anticancer therapeutics fail in clinical testing.
Poor preclinical strategies likely play a key role in this lack of success. Studies are not paying close enough attention to molecular targets which inevitably leads to poor efficacy. Target identification and validation are subsequently deemed essential to combating the painful attrition rates of modern pharmaceutical design. As described in Nature Chemical Biology, “know your target, know your molecule”, this can significantly improve derisking in drug development programs.
A molecular target is a biological entity in the body that is inherently linked to a specific disease process. We define these small molecules as targets if they are known to interact with, or be modulated by, a chemical compound. The genome revolution ushered in a new age of genetics-informed drug design based on extremely large datasets. The human genome encodes for more than 20,000 proteins, translating to numerous structures potentially able to serve as targets of a given drug.
This abundance can complicate target discovery as not all molecules can serve as a good drug target. Moreover, the potential polypharmacology of drugs can lead to unexpected side effects due to their specificity for more than one target. Hence the importance of robust target identification and subsequently validation.
Promising molecular targets show several key characteristics. Firstly, they must play a confirmed role in the specific pathology, or physiology, of the disease of interest. Secondly, the molecule’s three-dimensional structure must be available to assess its therapeutic activity. Thirdly, the target must show chemical evidence of potential activity with favorable toxicity. Both chemical and genetic target validation methods are used to inform critical decisions in the drug discovery process, mitigating the risk associated with blind decision-making.
There are two key methods of drug discovery available to biochemists and pharmaceutical developers today, but two of the overarching strategies are phenotypic screening and target-based discovery. These are methods that approach novel drug discovery from opposite ends of the workflow.
– Phenotypic screening describes a scenario where the ability of many compounds to alter a cell’s phenotype is tested in a mechanism-of-action agnostic manner.
– Target-based discovery defines the opposite approach where potential targets are identified first before a large compound database is screened for its ability to bind to the selected target.
There are pros and cons to each approach. For instance, phenotypic screening enables the identification of first-in-class targets. This is done in with an agnostic consideration of the mechanism-of-action, which can make it difficult to deconvolute the right target. The target-based approach, meanwhile, is ideal for drug identification specific to an individual target but it cannot address the problem of compound specificity or polypharmacology.
At Biognosys, we believe that the latest developments in proteomics herald an even greater breakthrough than those of genomics. We leverage our unique expertise in state-of-the-art proteomics to assist with drug discovery via target identification and validation pipelines.
One of our solutions is target deconvolution through Limited Proteolysis (LiP), which allows you to gain deeper insights into a drug’s specific mechanism-of-action as well as its toxicological profile. This novel, label-free approach to target identification is proprietary to Biognosys and has proven successful in a growing number of studies such as the recently published work in Nature Communications. If you would like to speak with us about deploying our experience in proteome analysis in your drug design studies, why not contact a member of the team today?
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