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Maarten Doornbos - Drug binding kinetics as predictor of potential medicines

Faster development of efficacious medicines; that is the goal of molecular pharmacologist Maarten Doornbos of the Leiden Academic Centre for Drug Research. He wants to find out which mechanisms influence the binding of drugs to a promising drug target in the body. That way, it will become easier to predict whether a potential drug will be effective or not. ‘I hope to speed up the process of drug development.’

Binding makes it work

In order for a drug to work, it needs to bind to a target in the body, called a receptor. Target binding kinetics describes this binding. It describes the rates by which molecules bind to and unbind from their target. As a result, pharmacologists can determine the ‘target residence time’ of a potential drug, which is an estimation of the time the molecule is bound to its target. For his thesis, Doornbos studied the molecular mechanisms of the mGlu2 receptor, a promising drug target for treatment of schizophrenia and depression. He found that for this drug target, the longer a drug resides at the target, the better it can do its job.

Target residence time

Although it seems very logical to measure the time molecules stay on their target, this is something that has been overlooked by the field. The lack of powerful assays that enable determination of these parameters has been a limiting factor until recently. ‘In collaboration with our industrial partner Janssen Pharmaceuticals we have set up a variety of novel assays to study various kinetic parameters, such as association and dissociation rate constants which can be used to determine the target residence time. We used these assays on a drug library of over two hundred novel molecules’, says Doornbos.

After Doornbos and his colleagues determined which parameters influence the kinetics of these molecules in the lab, they correlated them with their efficacy in an animal model. ‘We ultimately found that the target residence time of molecules that activate the mGlureceptor gives a rough prediction of the efficacy in the body.’ Hence, these parameters can guide pharmacologists towards more efficacious molecules, thereby ignoring molecules that are less likely to be efficacious.

Faster drug development

It is the first time this pharmacological concept has been studied for this specific class of drug targets. But more importantly, states Doornbos, the results strongly underline the importance of the addition of assays to determine binding kinetics for future drug discovery projects. ‘Drug development is a lengthy and expensive process. Incorporating the evaluation of binding kinetics in future drug discovery project might shorten this by enhancing the predictive value of in lab assays for efficacy the body and finally in patients. Ultimately, the results of the thesis contribute to bringing novel safe medicines to patients faster, using less laboratory animals.’

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