Kinetics for drug discovery – The first step towards an improved drug discovery paradigm
Supervisor: Indira Nederpelt
- Laura Heitman
Over the years the time a drug stays at its receptor, the so called drug residence time, has become an interesting and important parameter in the characterization of ligands (Fig. 1). Several studies have indicated that the long duration of action is an important feature of drugs designed to treat chronic illness contributing to prolonged efficacy and a once-daily, or even monthly, dosage form that increases patient compliance which is crucial for the management of diseases.
In order to incorporate optimized kinetics into the development of a new drug, design and validation of assays that help our understanding of drug-target residence time are essential. Therefore this project focuses on developing radioligand binding assays that can accurately determine the kinetics of agonists and antagonists for several different G protein-coupled receptors (GPCRs).
The GPCRs that are currently being investigated are the gonadotropin releasing hormone (GnRH) receptor, the tachykinin 1 (NK1) receptor and the dopamine D2 receptor. The GnRH receptor is mainly indicated in hormone dependent disorders such as precocious puberty and cancers of the breast and prostate. The NK1 receptor is primarily implied in the pathology of bronchial asthma, inflammatory bowel syndrome, gastrointestinal disorders as well as psychiatric disorders such as anxiety, schizophrenia and depression. The dopamine D2 receptors play a central role in the pathophysiology of psychosis, movement disorders such as Parkinson’s disease and addiction.
Figure 1: A schematic representation of the importance of kinetics in drug action. The chemical structure of a compound determines its dissociation kinetics, which in turn may translate into a desired and improved physiological effect (clinical efficacy).
- Cell culture
- Radioligand binding studies (equilibrium, kinetic)
- Functional assays (xCELLigence, luciferase reporter gene assay, IP 3 assay)