Universiteit Leiden

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Division of Drug Discovery & Safety

Binding kinetics

A tantalizing concept that has emerged in our recent research is binding kinetics. An important parameter is residence time (RT), a direct reflection of how long a drug stays bound to its target. This parameter is of crucial importance, because drug action lasts only as long as the receptor-ligand complex exists.

We obtained very intriguing results in the new field of Structure-Kinetics Relationships (SKR) with quite varied targets, such as the CCR2, GnRH, HCA2, A1 and A2A receptors. In these studies, we observed that small changes to the structure of a ligand can bring about changes in residence time of up to two to three orders of magnitude (from less than one minute to more than 10 hours). In the Figure are two high-affinity CCR2 antagonists, one that has been in clinical trials but having a modest residence time (MK-0812), another (compound 15a) developed by us from the clinical candidate with a very long residence time of over 10 hours. The latter compound proved to be very effective in a mouse model of atherosclerosis.

Related publications

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