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?
https://www.nature.com/articles/nchembio.1813
Proteins are among the most complex biomolecules in existence, comprising linear chains of just twenty different amino acids arranged into highly complex 3-dimensional structures. This structural diversity enables them to perform a staggering range of functions. Cellular messaging, enzymatic reactions, immunological responses, small molecule transportation: each of these processes are enabled and mediated by different proteins. Therefore, they are described as the functional units of all living organisms.
Proteomics is an advanced field of molecular biology focused on studying the entire set of proteins expressed by an organism, tissue, or cell at a particular moment.
A proteome is the entirety of proteins produced by a living system. It is analogous to the genome as the complete set of an organism’s genes. However, proteomes are subject to change in response to various internal and external factors, unlike genomes which are characterized by systemic stability.
Proteomics involves the set of proteins produced by an organism at a specific point in time. Slight changes to the proteome can have a dramatic impact on the state of a living system. Using proteomics to quantify thousands of proteins at a time allows us to identify aberrant pathways, to characterize the action of new compounds, or to uncover new biomarkers for clinical research.
Two different technologies are widely used to identify proteins in proteomics research: immunoassays, and mass spectrometry. Though enzyme-linked immunosorbent assays (ELISAs) and western blotting are staples of protein research, mass spectrometry-based proteomics offers the distinct advantage of protein-level quantification of thousands of proteins simultaneously at high speed and precision.
Mass spectrometry not only allows us to quantify the differential expression of the whole proteome but also understand post-translational modifications of proteins, protein-protein interactions and even – most recently – structural changes to the proteome. This is a highly specialized area, however, and warrants covering in more depth in future articles. Check back on our blog page in the coming months for more detailed proteomics insights.
At Biognosys, we have developed next-generation methods for measuring proteins at this proteome-wide scale. We deploy enhanced mass spectrometry with parallel data acquisition of peptide signals for the deepest possible coverage of complete proteomes. Using proprietary software for protein identification and quantification tools based on advanced AI and machine learning, this complex spectrum is then deconvoluted into individual quantities with capacity for over hundreds of thousands of different peptides per sample.
We offer a broad portfolio of products geared towards improving the accessibility of proteomics for researchers. These include sample preparation kits, peptide kits, iRT kits, and software solutions. The Biognosis team is also prepared to offer a choice of advanced services to assist with operations across the full drug discovery and development pipeline. Key areas of therapeutic interest that our team members excel in include:
– Oncology
– Neuroscience
– Immunology
– Rare diseases
– Chronic diseases
If you would like to learn more about how Biognosys pioneers next-generation proteomics solutions, simply contact a member of the team today.
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