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‘Take medicine target saturation into account’

Not taking into account the saturation of drug targets can lead to wrong conclusions about the duration of a drug's action. This is what former PhD candidate Wilbert de Witte writes together with the Leiden professors of pharmacology Meindert Danhof, Piet van der Graaf, and Liesbeth de Lange in Nature Reviews Drug Discovery.


In its review, the Leiden team looks at so-called binding kinetics: the speed at which a drug binds to its target in the body and at which it comes off again. Binding kinetics determines the residence time of a drug on the drug target and thus the duration of the drug's action, according to a much quoted publication by Copeland and colleagues from 2006.

The Leiden researchers are now commenting on this. 'We emphasize that binding kinetics is not the only process that determines the duration of a drug's action', says the Leiden team. 'Amongst others, saturation of the binding to the drug target can also lead to a longer duration of action. If this is not taken into account, there is no proper understanding of the relationship between drug properties, the residence time of a drug on its target, the duration of action of the drug and the dosage regime', the Leiden pharmacologists state.

The journey of a drug through the body

The binding kinetics of a drug to the target and the saturation of that target are just two of the processes that influence the precise effect and duration (or lack thereof) in the body. There are also the speeds at which the drug is absorbed into the body, distributed over the tissues and eventually broken down again, and the speeds at which the drug comes near the target and leaves it again. The interplay of these factors determines the concentration of the drug at different places in the body over time and possibly also the course of the effect. This is one of the reasons why it is difficult to directly compare measurements of binding kinetics in the lab with measurements in subjects or patients.

How does a medicine work?

Simply put, a drug fits on its target like a puzzle piece. This creates an interaction that brings about a change, and ultimately leads to the desired effect. Take aspirin for example: this drug has its fever-reducing, analgesic, anti-inflammatory and blood-thinning effect thanks to the inhibition of an enzyme in the body. This enzyme normally causes fever, pain and platelet sticking.

How effective is a medicine?

The better the piece of the puzzle fits, the longer it stays on its target. When a drug remains bound to the target for a longer period of time, the effect of the drug can last longer. 'A long stay of a drug on its target is interesting for the chronic therapeutic applications of a drug,' says the Leiden team. 'This means that the pharmaceutical industry also pays a lot of attention to determining the binding kinetics of the drugs to be developed.'

Full is full

Besides binding kinetics, the saturation of drug binding to the target is important, according to the Leiden authors. What exactly does this mean? Suppose the target of a drug is a specific receptor in the body. In the case of saturation, all these receptors are occupied by that drug. As an example, the Leiden review gives the drug aprepitant; a drug that is often used to suppress the nausea associated with chemotherapy. In a preclinical study, the duration of action of aprepitant and two similar substances was investigated. The long duration of action of aprepitant only was attributed to a long residence time of this drug on the neurokinine-1 receptor. However, the Leiden team shows that the long duration of action is the result of a prolonged high concentration of aprepitant around the receptor in the brain. This leads to prolonged saturation of the receptor, resulting in a long duration of action.

Publication Leiden team (2019)


Publication Copeland et al. (2006)


Why is this discovery important?

Medicinal chemists design molecules with certain properties, which are then tested for their efficacy as a medicine. For them, it is important to know the relationship between molecular properties and the behaviour of the molecule in the body, often with the aim of achieving a long duration of action of such a potential drug. By not considering any saturation of a target protein for the possible long-term action, wrong conclusions can be drawn about the relationship between molecular properties and binding kinetics. In addition to drug development, the discovery is also important for drug administration. Without taking possible saturation into account, it may happen that the dose frequency is not right or suboptimal.

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