The Depixus blog – seeing biology as it really happens

January 22, 2025

Using Depixus MAGNA One™ to explore biomolecular interactions and accelerate drug development

Life runs on biomolecular interactions. A complex network of interactions between DNA, RNA, proteins, and other biomolecules underlies all biological processes. Studying these interactions is key to understanding how these processes work in health and disease, and for the development of more effective treatments.

New technologies and therapeutic modalities are expanding the drug target universe to include previously ‘undruggable’ targets such as protein-protein interactions and RNA.

Interactomics, the study of interactions, is helping to not only identify these novel drug targets but also measure and analyze how potential drug candidates interact with them.

However, studying these interactions is easier said than done.

Current methods for analyzing biomolecular interactions are limited

Reliable, detailed data about how ligands interact with their targets to inform hit-to-lead selection is a major bottleneck, slowing down drug development pipelines.1 Unreliable data can also lead to sub-optimal drug candidates progressing into preclinical or even clinical studies, resulting in costly failures further down the track.2

When hits are identified from a screening assay, researchers need to determine which of these is the most promising lead to take forward for further optimization. But current analytical technologies often provide limited information about how candidate drugs bind to and interact with their targets.

Conventional methods for analyzing biomolecular interactions can be:

  • Indirect, relying on surrogate measurements rather than direct read-outs of drug-target interactions.
  • Static, providing a fixed snapshot of a drug bound to a target rather than measuring dynamic binding kinetics.
  • Unrepresentative, producing an average over thousands of molecules rather than individual measurements.

Bulk techniques that produce averaged data, such as surface plasmon resonance, isothermal titration calorimetry or microscale thermophoresis, may miss crucial information about rare binding events. Static approaches such as X-ray crystallography can’t provide information about binding kinetics. And methods that directly probe individual biomolecular interactions, such as atomic force spectroscopy or optical tweezers, can only analyze a small number of molecules at a time.

A technology capable of directly measuring individual drug-target interactions at scale that provides detailed kinetic information would ensure faster hit-to-lead and lead optimization, significantly accelerating drug development.

Depixus MAGNA One™ is the solution. Here are some examples of what it can do.

Depixus MAGNA One provides direct, dynamic, representative data about biomolecular interactions

Based on magnetic force spectroscopy (MFS), Depixus MAGNA One is the first instrument capable of directly measuring biomolecular interactions across thousands of individual molecules in real time, producing direct, dynamic data without relying on surrogate readouts.

Depixus MAGNA One simultaneously measures kinetic data from thousands of individual molecules in parallel. This method captures the precise details of each interaction, making sure you get representative, information-rich data to accelerate the discovery and development of drugs for previously undruggable targets.

Watch this animation to learn more about how Depixus MAGNA One works:

Studying protein-protein interactions with Depixus MAGNA One

The pharmaceutical industry has traditionally focused its drug development efforts on small-molecule therapeutics targeting proteins with well-defined drug-binding pockets, such as receptors, enzymes, and ion channels.

While this approach has led to many successful drugs, only a minority of disease-associated proteins can be targeted in this way. Of the ~20,000 protein-coding genes in the human genome, around 4,500 are considered to be ‘druggable’. Yet currently fewer than 700 are targeted by FDA-approved drugs.3

Attention is now turning to the possibility of drugging the protein-protein interactions (PPIs) that are essential to many biological processes. Developing drugs that target these interactions, such as inhibitors, molecular glues, or PROTACS, opens up a new world of potential therapeutics.

Depixus MAGNA One makes it possible to measure the strength of interactions between two individual proteins and investigate the impact of small molecules and other ligands, transforming PPI drug discovery.

The detailed data provided by Depixus MAGNA One gives direct, dynamic, real-time insights into the strength of protein-protein interactions and ternary complexes, binding kinetics and additional thermodynamic parameters for thousands of individual interactions in parallel.

Developing novel RNA-targeted therapeutics with Depixus MAGNA One

Proteins aren’t the only biologically active molecules within cells. RNAs are becoming increasingly prominent as a promising drug target – of the estimated 140,000 4 different RNAs that make up the human transcriptome, less than a fifth are expressed as proteins.5

With Depixus MAGNA One, you can probe individual RNA-ligand interactions and gain insights into the mechanism of action, driving forward RNA-targeted drug development.

For example, in a study published in Nature Communications,6  leading RNA researcher Professor Jay Schneekloth used data from our magnetic force spectroscopy (MFS) technology to investigate how small molecules can induce conformational changes in the PreQ 1 bacterial riboswitch.

We were able to show that two ligands with apparently similar effects had different mechanisms of actions – a distinction that would have been missed using other analytical methods.

Depixus MAGNA One: See biology as it really happens

Depixus MAGNA One offers direct insights into the world of biomolecular interactions.

By directly studying these dynamic interactions at scale, our technology will open up new avenues in fundamental biological research and accelerate drug development across a wide range of diseases and novel modalities.

Get in touch to find out how you can explore new targets and develop more effective therapies with Depixus MAGNA One.

References:

1. Hoffer L, et al.. Chemistry-driven Hit-to-lead Optimization Guided by Structure-based Approaches. Mol Inform. 2018 Sep;37(9-10):e1800059. doi: 10.1002/minf.201800059

2. Sertkaya A, Beleche T, Jessup A, Sommers BD. Costs of Drug Development and Research and Development Intensity in the US, 2000-2018. JAMA Netw Open. 2024;7(6):e2415445. doi: 10.1001/jamanetworkopen.2024.15445

3. Sharma KR, et al.. Illuminating the druggable genome: Pathways to progress. Drug Discov Today. 2024 Mar;29(3):103805. doi: 10.1016/j.drudis.2023.103805

4. Gonzàlez-Porta, M., Frankish, A., Rung, J. et al. Transcriptome analysis of human tissues and cell lines reveals one dominant transcript per gene. Genome Biol 14, R70 (2013). doi: 10.1186/gb-2013-14-7-r70

5. Clamp M, et al. Distinguishing protein-coding and noncoding genes in the human genome. Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19428-33. doi: 10.1073/pnas.0709013104

6. Parmar S, et al.. Mechanistic analysis of Riboswitch Ligand interactions provides insights into pharmacological control over gene expression. Nat Commun. 2024 Sep 17;15(1):8173. doi: 10.1038/s41467-024-52235-3