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Pharmaceutical science

Bound to work better

Studying how long a drug stays bound to a receptor can help scientists develop more effective medicines. 

One of the best-selling antihypertensive drugs candesartan lowers blood pressure more effectively than any other drug in its class. One possible reason for this effectiveness is its binding kinetics: the active agent spends several hours bound to its target receptor, the angiotensin II receptor, compared with just a few minutes for losartan — another drug in its class.

“It has been postulated that for this reason candesartan is advantageous because it produces more prolonged blood pressure lowering, meaning that it has greater efficacy at lower doses and retains efficacy in the event of a missed dose,” explains Mike Waring, principal scientist at AstraZeneca, which markets the drug as Atacand.

Over the past five years, scientists have increasingly been studying drugs’ binding kinetics, which determine how fast a drug and its receptor associate (K on ) and dissociate (K off ). There is mounting evidence to suggest that the ‘residence time’ — a term introduced by Robert Copeland and colleagues at GlaxoSmithKline in 2006 to describe the time a drug remains bound to its target — has a strong influence on a drug’s clinical success. 

Only 10% of drug candidates that enter phase I trials end up being approved by the US Food and Drug Administration[1] . To try to reduce this attrition, pharmaceutical companies have started studying binding kinetics in drug discovery programmes, but this is not yet being systematically applied because of a lack of experience and uncertainty about its importance.

“Until recently, binding kinetics has been ignored — the least we can do is pay more attention to it,” says Ad IJzerman, a medicinal chemist at the University of Leiden in the Netherlands. “We want to convince the research community you can’t live without it.”

Source: Ad lJzerman / University of Leiden

Ad lJzerman, a medicinal chemist at the University of Leiden in the Netherlands, is a lead researcher in K4DD

Molecular basis

The concept of binding kinetics dates back to work in the early 1960s by William Paton, one of the pioneers of pharmacology [2[9]] [3] . In one paper, Paton postulated a rate theory, which uses the interaction of a drug with its receptor to explain drug action, potency and speed of offset3 .

Several important advances have since led to the current interest. In 1984, Motulsky and Mahan laid the theoretical foundations for binding kinetics and outlined the equations used to measure it[4] . And in 2004, David Swinney highlighted the importance of the biochemical mechanism of drug action in drug efficacy and safety[5] .He described the potential discovery and development risks associated with the binding mechanism of drugs and proposed simple rules to minimise them.

However, researchers have tended to focus on the strength of the binding between a drug candidate and its target (the affinity), rather than on how long the drug remains bound to the target (the residence time). The affinity of a drug is the concentration at which 50% of the target receptors are occupied. This is the ratio of K off to K on but says nothing about the binding kinetics.

“Initially, researchers believed that if a drug has good affinity, it would have a good effect. But this is not the case,” says IJzerman. “You can have a good website, but if you don’t stick to its pages long enough, you probably won’t have learnt that much.”

He explains that two drugs can have the same affinity to a receptor but have different binding kinetics, and these may affect the drug’s efficacy. “If you focus on affinity alone, you’d have difficulty in selecting promising drug candidates,” he says.

Four key factors are thought to play a part in controlling drug–receptor binding kinetics at a molecular level: molecular size, hydrophobic effects, electrostatic interactions, and conformational fluctuations[6] .

“It has been observed that as you increase the hydrophobicity of a drug, it creates a higher energy barrier; in other words, it makes it harder for the drug to dissociate from its receptor,” says Waring. “The hydrophobic parts of a drug are shielding the hydrogen bond from the water.” He adds that the conformational flexibility of a drug is also being studied to see how it affects the binding kinetics. In general, more flexible compounds tend to have longer residence times at the target receptor.

Pros and cons

Of the medicines that have been studied for their binding kinetics, several have slow dissociation rates from their targets. In some cases this leads to better efficacy, but it can also cause side effects.

The bronchodilator tiotropium, for example, has a dissociation half-life of 34.7 hours[7] .This is beneficial for the treatment of chronic obstructive pulmonary disease because patients need a long-acting bronchodilator. “In other words, it has a long residence time at the muscarinic M3 receptor, which is what is wanted here,” says IJzerman.

However, the antipsychotic drug haloperidol has a long residence time on the dopamine D2 receptor, causing a range of side effects, such as the symptoms of Parkinson’s disease and tardive dyskinesia. “The newer atypical antipsychotics have a shorter residence time than haloperidol, and that may be why they have a reduced incidence of these side effects,” explains IJzerman.

Scientists are trying to improve their understanding of binding kinetics by looking at how small molecules interact with their targets, and how this affects residence time and clinical efficacy. They are also seeking to develop assays that could easily be incorporated into drug development to reliably predict a molecule’s kinetic properties. The assays currently used are laborious and time-consuming, and are often expensive. They allow tens of thousands of compounds to be run in a reasonable timeframe, but researchers want to raise that to hundreds of thousands.

Working together

In a bid to address these questions, the Kinetics for Drug Discovery (K4DD) consortium was set up in November 2012 to run for five years. “We knew binding kinetics were important in optimising compounds, but we struggled in making headway on what drives K on and K off ,” says Waring, who proposed the project. “There was no general understanding on how we could modulate binding kinetics in a rational manner.”

The K4DD consortium has received a total of €20.9 million from the Innovative Medicines Initiative (IMI), a public–private partnership funded by the European Commission, and member companies of the European Federation of Pharmaceutical Industries and Associations. The consortium involves seven large pharmaceutical companies, ten academic institutions and three small- to medium-sized enterprises, which have agreed to share information on binding kinetics.

The project is currently studying between 10 and 20 drug targets, including kinases, proteases, heat shock protein 90 and G-protein-coupled receptors (GPCRs).

Source: Benjamin Tehan / Heptares Therapeutics.

Caffeine (red, blue, green atoms) bound to a G-protein-coupled receptor (salmon ribbon) within a lipid bilayer (white)


“The drug targets are important, but we don’t necessarily think we are likely to see any new commercial drugs coming out of this project,” says Waring. “Our primary intention is to use these test cases to develop an understanding of how these compounds interact with their receptors and how this affects residence time.”

The GPCRs are linked to many diseases and form the largest group of targets for existing drugs, as about 30–40% of all marketed drugs act by binding to them. They include beta-1 receptors, histamine receptors and the dopamine-2 receptor.

We want to convince the research community that you can’t live without it.

Heptares Therapeutics, one of the commercial partners involved in the project, is creating new medicines that target previously undruggable or challenging GPCRs. Rob Cooke, the company’s head of biomolecular structure, says: “These receptors play a major role in the function of the human body, and increased understanding of how they interact with drugs will greatly affect drug discovery.”

IJzerman, who is a lead researcher in K4DD, says the consortium would like to move from using cell and membrane assays to using patient data. “We want to learn from clinical studies that have been done, and also from studies of failed drugs. Did the compounds have the wrong binding kinetics? It would be great to be able to learn from the failures,” he says.

From theory to drugs

Pooling global scientific resources makes sense because it’s a big task and expertise is scattered across numerous smaller projects and organisations. “By bringing together these diverse groups, K4DD is set to give a major boost to this important area of drug development,” says Michel Goldman, executive director of the IMI.

For example, not enough is known about the kinetic parameters required to create successful drugs. It’s not clear “whether we can turn this information into actual design principles” for new drugs, says IJzerman, “and whether this molecular mechanism of action is dictating the physiological outcome of drug administration to a patient.”

Source: Mike Waring / AstraZeneca

Mike Waring, principal scientist at AstraZeneca, proposed the K4DD project to increase understanding of how to modulate binding kinetics.

Trevor Howe, scientific director of external innovation at Janssen Pharmaceutica, is a member of the consortium who has worked with Waring on the idea. “I got involved not because binding kinetics is a sexy area at the moment, but everyone is wondering whether having a long Koff rate for a ligand can provide a measurable and consistent means of finding better drugs,” he says.

“We still don’t know precisely the parameters we need to adjust in order to design ligands which  target a structure-kinetic relationship compared to a structure-activity relationship. We want to know how binding kinetics alters a pharmacodynamic response, in other words, creates a clinical response.”

Swinney, who is on the scientific board for K4DD, applies binding kinetics to the discovery of compounds to treat rare and neglected diseases at the non-profit Institute for Rare and Neglected Diseases Drug Discovery (iRND3), based in Mountain View, California. For example, the iRND3 is working on possible treatments for sleeping sickness, which is caused by the parasite Trypanosoma brucei . A long residence time translates to more effective killing of the parasites.

The next steps

The consortium met in late June 2014 in Frankfurt, Germany, for the fourth of its six-monthly reviews. This was the first meeting to focus solely on its scientific findings. After five years the consortium plans to create a database of the residence times of thousands of compounds and place it in the ChEMBL open-access database on biologically active molecules, which is maintained by the European Bioinformatics Institute in Cambridge, UK. 

“Some compounds will have clinical application, while others will not, but they will still tell us a lot about residence time,” says IJzerman. “In the end, I hope that the entire research community will appreciate the importance of kinetics, and that others will also start adding kinetic data to the database.”

Swinney hopes the database will be easy to use. “I have already met investigators who would like to use the data as training sets to test and validate new ideas,” he says, adding that the consortium will teach a new generation of scientists to identify effective ways of applying binding kinetics to increase success in drug discovery.

Ultimately, the success of the project rests on whether binding kinetics can be used to better inform the design and development of drugs. This will help the pharmaceutical industry to reduce its drug attrition rates and costs by weeding out ineffective or unsafe molecules earlier in the drug discovery process. As IJzerman says: “We are now beginning to appreciate that a drug’s dissociation rate from its target is key to understanding how we can discover better drugs and reduce attrition rates.”

Elizabeth Sukkar is deputy news editor of The Pharmaceutical Journal.

Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2014.20065576

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