We have just launched Euretos Perspectives: a bi-weekly view on key aspects of data-driven target selection in drug discovery. Our first perspective is on phosphorylation as a key target assessment criterion in certain therapeutic contexts such as Parkinson’s disease. Enjoy the read and subscribe if you want to stay tuned!
I was talking to one of our customers recently who we are working with on target discovery and assessment. They mentioned that at least as important as getting novel target predictions using Euretos' computational models is our ongoing collaboration to assess these target candidates. Especially data-driven insights into the underlying disease biology is essential for them to decide which targets to move forward in the drug discovery process.
With a 70% failure rate in clinical trials due to a lack of efficacy or lack of safety of the drug target, the importance of these decisions are enormous and every bit of insight is more than welcome, they said.
Especially data-driven insights into the underlying disease biology is essential for them to decide which targets to move forward in the drug discovery process.
Drug target candidates can arise from various sources, such as biochemical screens, analysis of patients' tissue or cell contents, or computational methods such as our predictive AI models. The team of researchers responsible at our client is often confronted with a large unranked list relevant target options for assessment. They need to decide on the most promising candidates to include in the next step of drug development. And they need to decide fast, and with confidence.
For a systematic, repeatable, and efficient assessment, data-driven methods can provide insights in the different assessment criteria. These include insights in disease link, safety, technical aspects such as drug ability, and strategic considerations such as market size, competition, and patents.
Let’s take a closer look at one of these criteria: the link of the target to the disease pathology, which is a one of the key factors related to the potential target efficacy. This starts with understanding the protein function and its relation to the molecular network in which it functions, understood in the relevant cellular context. By applying data driven methods that simulate target behavior in the context of human biology, it is possible to provide insights in the molecular mechanisms at play and role of target candidates within these mechanisms.
Protein function, structure, stability, and localization are often influenced by post-translational modifications (PTMs), and they are critical in regulating many biological processes. The analysis of PTMs in target candidates contributes to both target-disease linkage as well as understanding technical aspects of drug ability.
Having the ability to quickly add such detail into a customizable biological knowledge graph and making it available in your target assessment process saves precious time and effort and significantly increases confidence in the drug target selection decision.
In relation to drug development, one of the most important PTMs on proteins is phosphorylation. The addition of a phosphate group to a protein by kinases is the most common PTM. It plays a key role in signal transduction and cell cycle regulation and therefore often implicated in disease processes. Many drugs have been developed that target protein kinases, making them a promising therapeutic target.
In Parkinson's disease for example, one of the essential processes appears to be the phosphorylation of Alpha-synuclein. Alpha-synuclein is a protein that is found abundantly in the brain and is thought to play a role in synaptic function. In Parkinson's disease, phosphorylated alpha-synuclein aggregates to form Lewy bodies, which are pathological hallmark features of the disease.
Advances in mass spectrometry-based proteomics have enabled large-scale identification of phosphorylation sites in cells and tissues, and in substrate specificity of protein kinases. From connections of these data to cell type specific expression profiles and localization information, emerges the biological story behind the protein kinase target candidates.
The role of phosphorylation of Alpha-synuclein in Parkinson's disease is an example of how very specific target assessment criteria can be, depending on the disease and therapeutic context. Having the ability to quickly add such detail into a customizable biological knowledge graph and making it available in your target assessment process saves precious time and effort and significantly increases confidence in the drug target selection decision.