Kinetics for Drug Discovery


Start Date
End Date
IMI1 - Call 4
Grant agreement number

Type of Action: 
RIA (Research and Innovation Action)

IMI Funding
8 286 930
EFPIA in kind
9 831 318
2 742 002
Total Cost
20 860 250


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

Achievements & News

‘We brought target binding kinetics to the international research community’ – an interview with the K4DD project coordinators
March 2019

Drugs work by binding with molecules in the body to either block or alter 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. In an interview with the IMI Programme Office, project coordinator Anke Mueller-Fahrnow of Bayer, and academic coordinator Ad IJzerman of Leiden University explain how the project transformed the field and could lead to more effective drugs in the future. ‘Thanks to K4DD, more and more scientists within pharma companies but also in academia are aware of the importance of binding kinetics,’ said Mueller-Fahrnow. ‘So something that has really been pretty exciting and novel ten years ago, is something that is now broadly appreciated and used in the drug discovery process.’

K4DD infrared sensor could aid in drug discovery
September 2018

Scientists from IMI’s K4DD project have developed an infrared sensor that rapidly reveals how a drug binds to its target and how long that effect lasts. The tool, which could aid in the development of more effective drugs with fewer side effects, is described in a paper in Angewandte Chemie. ###Many drugs take effect when they attach themselves to a specific protein, thereby blocking or altering its activity. In cases where the drug binding is accompanied by structural changes of the protein, it is important to obtain information about these structural changes. Current methods to assess the nature of these structural changes need weeks or even months to deliver results. The new technique delivers results in just minutes. In the sensor, the target protein is bound to the surface of a crystal, which is rinsed with solutions containing a drug that should attach to the protein. An infrared light is shone through the crystal; any changes to the protein structure caused by the drug are detected by a sensor. The team tested their device on medicines designed to affect the heat shock protein HSP90, which is implicated in a number of diseases including cancer. The device delivered the same results as conventional tests and provided new information on the activity of 11 additional HSP90 inhibitors. The nature and duration of a medicine’s attachment to the target protein can influence how effective a medicine will be, and how often it will need to be taken. The authors of the paper conclude: ‘Particularly when scaled up in an automated screening platform, our method could be used to identify new drug candidates in the early drug-discovery process.’

K4DD findings suggest new strategy for drug discovery
January 2018

IMI’s K4DD project has shed new light on the factors that influence interactions between medicines and their targets. The findings, published in Nature Communications, could open up new avenues for drug discovery. Drugs work by binding with proteins that are implicated in disease and so preventing them from working. Much drug discovery work focuses on optimising the interactions between drugs and their targets. ###For a long time, researchers thought that the more tightly a drug binds with a target protein, the more effective it will be. The K4DD project set out to study in detail the kinetics of the interactions between drugs and targets. In this paper, the team applied state-of-the-art experimental and computational approaches to study the kinetics of anti-cancer medicines designed to block the action of a drug target called heat shock protein 90 (HSP90). Blocking the action of HSP90 can disrupt the cell cycle and so stop the growth of cancerous tumours. X-ray crystallography revealed that the binding pocket of HSP90 is lined by a region that can take the shape of a helix or loop, depending on the inhibitor under study. Notably, the drugs that bind with the comparatively flexible helix remain bound for longer. ‘We were really surprised when we found out that an important contributor to the long residence times was the greater mobility of the helical region of the binding pocket when the inhibitor bound,’ said Rebecca Wade of the Heidelberg Institute for Theoretical Studies, one of the co-authors of the paper. Using as an analogy a ski boot with an adaptable inner liner that continually adjusts to the foot, rhe researchers suggest that scientists can therefore consider less rigid protein targets and identify molecules that stabilise more mobile forms of the protein upon binding.

K4DD project results in a PhD thesis
April 2017

Binding interactions between neuropeptides (the body’s neural signalling molecules), drugs and their target molecules were the focus of the first PhD thesis defence resulting from IMI’s K4DD project. Indira Nederpelt of Leiden University was the author of the thesis which has already resulted in six peer-reviewed publications, with more to come.### The thesis has helped expand the toolbox of available methods which allow more accessible measurements of how drugs and their target molecules interact in the body. According to Ad IJzerman of Leiden University, K4DD’s managing entity, ‘Indira’s study falls perfectly within K4DD's ambition to transform binding kinetics into traditional, indispensable, drug discovery parameters and thereby improve the success rate of drug discovery in the future.’ The main goal of the K4DD project is to improve our understanding of how potential drugs bind with their target, and develop methods and tools to allow researchers to study drug-target interactions with greater ease. An important part of the project is its educational programme, which has funded more than 20 post-docs and PhD students in the last five years. The programme has provided fellows with the opportunity to gain a thorough understanding of the connection between drug discovery and drug development by offering them an extensive drug discovery course and several binding-kinetics-oriented symposia. Fellows also got the opportunity to improve their soft skills by taking a scientific writing course, career workshops and a presentation workshop. Several more PhD theses are expected to be successfully defended by the end of this year.

New K4DD math formula predicts duration of potential drug effect
February 2017

When researchers assess potential new drug candidates, it is not only important for them to know whether a particular drug molecule will bind with its biological target in the body, but also with what strength and speed this binding will occur. If the binding is weak and short-lived or it takes too long for the molecule to bind with the receptor, the drug won’t be very effective in treating patients.### In order to improve the assessment of potential new medicines, K4DD project fellow Wilbert de Witte from the Leiden University has published a new mathematical model which predicts how long a drug effect will last. The model takes into account several important variables such as the concentration of the drug in the body and its rate of binding and unbinding with the biological target, and analyses them in order to predict the duration of the potential drug effect. This mathematical approximation, which was published recently in the journal Trends in Pharmacological Sciences, gives an idea earlier in the drug development process on whether a drug is worth pursuing or not. It has the potential to reduce waste and increase the likelihood of getting better and safer drug candidates for the benefit of patients. ‘Even though only one partner is responsible for this paper, the idea to initiate this particular approach was created during discussions within the consortium,’ said Tale Sliedrecht of Lygature, one of the K4DD project partners. ‘By creating an open, pre-competitive environment, researchers from different areas were able to share their insights and needs. The model we came up with is quite significant: the study has led to a lot of debate within the consortium and was highly appreciated by scientists in K4DD’. The study contributes to the overall goal of the K4DD project which is to improve our understanding of how potential drugs bind with their target, and develop methods and tools to allow researchers to study drug-target interactions with greater ease.

K4DD study sheds light on drug target for Parkinson’s and cancer
November 2016

Drugs work by binding with molecules in the body to either block or alter the action of the target molecule. IMI’s K4DD project works to understand this complex and dynamic relationship, and recently the project reported a big step forward – a step which could lead to the development of safer and more effective drugs for a broad range of diseases. ###Two of the K4DD project partners, Leiden University in the Netherlands and a British SME Heptares Therapeutics, worked together to improve the understanding of the so-called adenosine A2A receptor, a therapeutic target for several diseases including Parkinson’s and cancer. Currently many efforts are directed towards discovering new therapeutic molecules which could bind with this receptor, but the desired properties of such molecules are not well understood. By developing a series of molecules, which were similar in structure but had different dynamics of binding with the adenosine A2A receptor, the K4DD partners gained new, significant insights into how this receptor interacts with different molecules. This in turn enabled them to understand factors which cause some potential drug molecules to disconnect from the receptor, knowledge which can probably be applied to similar mechanisms which exist in a broad range of other receptors similar to A2A. This will lead to the development of safer and more effective drugs to target receptors in general. According to the project partners, the collaborative nature of the IMI project was the key to achieving this success. ‘The K4DD project partners have created an open environment in which the sharing of knowledge, results and resources is continuously stimulated’, said Tale Sliedrecht of Lygature, one of the project partners. ‘In this particular study two partners with different specialties combined forces and generated new findings which would not have been possible without the collaboration.’

K4DD professor knighted
June 2014

Meindert Danhof, Professor of Pharmacology at the University of Leiden and a partner in IMI’s K4DD project has been appointed as Knight in the Order of the Netherlands Lion.### Professor Danhof received the royal decoration for his research and development of models that have made an important contribution to better predicting the efficacy of medicinal products.

Within the K4DD project framework, Professor Danhof's group, together with other academic and pharmaceutical industry research groups, focuses on better understanding the kinetics of the interaction between a drug molecule and its disease target within the human body. There is growing evidence that this kinetic information is important to predict how fast a drug effect will appear in a patient, and how long it will last.

Translating research findings from the ‘test tube’ stage to the clinical stage requires comprehensive pharmacological models. These models not only need to take into account the interaction of a drug with its disease target at a cellular level, but also to account for the human body’s reaction to the drug. Ultimately, the aim of pharmacological models developed within K4DD is to further optimise the prediction of the efficacy of medicinal products early on in the drug discovery process.

Save the date: K4DD end meeting in October
In the last five years, IMI’s K4DD project has made a significant contribution to helping scientists understand how drugs bind with their targets in the body. This year the project is coming to a close and will share some of its achievements and lessons learned at a closing conference from 16 to 18 October in Berlin, Germany, ###which will be open to the entire scientific community. The event will feature distinguished speakers from a range of pharmaceutical companies and universities, including Leiden University, the University of Vienna and AstraZeneca. The keynote speech will be delivered by Piet van der Graaf, professor of systems pharmacology at Leiden University and one of the leaders in the field. Registration is now open via the project website.
(March 2017)

Participants Show participants on map

EFPIA companies
  • Astrazeneca AB, Södertälje, Sweden
  • Bayer Aktiengesellschaft, Leverkusen, Germany
  • F. Hoffmann-La Roche AG, Basel, Switzerland
  • Glaxosmithkline Research And Development LTD., Brentford, Middlesex, United Kingdom
  • Janssen Pharmaceutica Nv, Beerse, Belgium
  • Merck Kommanditgesellschaft Auf Aktien, Darmstadt, Germany
  • Sanofi-Aventis Deutschland GMBH, Frankfurt / Main, Germany
Universities, research organisations, public bodies, non-profit groups
  • Fraunhofer Gesellschaft Zur Forderung Der Angewandten Forschung Ev, München, Germany
  • Hits Ggmbh, Heidelberg, Germany
  • Imperial College Of Science Technology And Medicine, London, United Kingdom
  • Ruhr-Universitaet Bochum, Bochum, Germany
  • Stichting Lygature, Utrecht, Netherlands
  • Stichting Vu, Amsterdam, Netherlands
  • The University Of Nottingham, Nottingham, United Kingdom
  • Universitat Wien, Vienna, Austria
  • Universiteit Leiden, Leiden, Netherlands
  • University Of Dundee, Dundee, United Kingdom
  • University of Oxford, Oxford, United Kingdom
Small and medium-sized enterprises (SMEs)
  • Heptares Therapeutics Limited, Welwyn Garden City, United Kingdom
  • Sierra Sensors GmbH, Hamburg, Germany
Project coordinator
Anke Mueller-Fahrnow
Bayer AG
Managing entity
Ton Brouwer
Universiteit Leiden