Kinetics for Drug Discovery

Drugs work by binding with molecules in the body and either blocking or altering the action of the target molecule. IMI’s K4DD project improved our understanding of how potential drugs bind with their target, and developed methods and tools to allow researchers to study drug-target interactions with greater ease. These tools will help scientists to determine whether a drug candidate is likely to be safe and effective much earlier in the drug development process.

A major difficulty for those attempting to develop new medicines is predicting whether or not a potential drug will be effective. Currently, researchers spend a lot of time studying how strongly a potential drug binds with its target. However, less attention is given to the question of how long the drug remains bound to the target.

Nevertheless, there is mounting evidence to suggest that the kinetics of the interaction between a drug and its target have a strong influence on the clinical success of a drug. For example, studies have shown that many recently marketed drugs have improved kinetic profiles. This is logical; as drugs only work when they are bound to the target, the lifetime of the drug-target complex is key to the success of a drug.

By bringing together a diverse group of experts from industry, academia and small and medium-sized enterprises (SMEs), K4DD set out to give a major boost to this important area of drug development. One of the main project achievements is a better understanding of binding kinetics, and exactly how small molecules interact with their targets. The project also helped raise awareness of the importance of considering the kinetic aspects of drug-target interactions throughout drug development.

Development of tests systems and new technologies

In order to implement target binding kinetics in the drug discovery process, researchers first had to develop test systems (assays) that specifically measure the kinetic properties of a compound. K4DD developed several assays, which have now been published and can be used on a routine basis by everyone in the scientific community. Furthermore, K4DD project scientists have already been using these systems to deepen their understanding of compound properties that trigger certain behaviour, therefore laying the foundation for a broader use.

SMEs outside of the project have further built on these ideas by developing and commercialising several off-the-shelf kits for analysing drug-protein binding kinetics. An SME within the consortium, Sierra Sensors, also developed a molecular affinity screening machine that can be used for measuring drug-protein binding kinetics data in a high-throughput format.

A database, a toolbox and other achievements

Other important project achievements include:

  • a comprehensive database of kinetic data which is now publicly available through ChEMBL;
  • a toolbox of computational methods for studying molecular binding kinetics, and the computational tools that employ them;
  • an improved understanding of how drug molecules bind with specific receptors that are important therapeutic targets for diseases such as Parkinson’s and cancer.

The project also resulted in the creation of a spin off. Called Phenaris, it will develop ToxPHACTS, a software that will combine K4DD and eTOX project outputs with the Open PHACTS discovery platform.

For the benefit of industry, academia and SMEs

The academic partners within the project benefited from getting to know how things work in industry. They also got access to industry resources such as compounds, cells and reagents, which facilitated their work in the field and enabled them to publish papers with more information and impact than they could have generated otherwise. The project also resulted in multiple PhD defences and some of the research fellows later found jobs in industry.

The industry benefitted from project outputs, such as assays for testing kinetics. Thanks to the K4DD project, most pharmaceutical companies, and all of the ones which were in the project, started considering the impact of binding kinetics in early drug discovery.

The SMEs within the project benefitted from the network that has been established. They developed promising new technologies and one SME, Sierra Sensors, has even been acquired by a larger company, a manufacturer of scientific instruments.

Next steps

One of the most important project legacies is raising the awareness of target binding kinetics. Now that the project is over, this awareness raising will continue through papers that have been published and through about 30 research fellows who were trained within the project and will continue to be the ambassadors of target binding kinetics.

The project will also continue to have impact through assays and technologies developed within the project and through the K4DD database, which will be an invaluable asset for future research.

Read the interview with the project coordinators

Source: IMI Innovative Medicines Initiative