Leiden Academic Centre for Drug Research (LACDR)

Current research focusses on the development and use of a metabolomics-based study of disease pathology and physiology, and to discover biomarkers for the early diagnosis of diseases and the prediction of pharmacological treatments. This knowledge is used to better understand and optimize current pharmacological treatments, or to develop novel pharmacological treatments. For this, Thomas has developed a wide range of mass-spectrometry based metabolomics platforms suitable for clinical and preclinical samples. Together, Piet Hein and Thomas are developing a systems pharmacology approach to (i) identify novel drug targets, (ii) assess the target engagement of existing or novel drug candidates, and (iii) translate in-vitro and in-vivo findings via quantitative modelling to clinical use. In (inter)national collaborations with academic and industrial partners they are involved in various systems biology projects aiming to develop novel treatments of multifactorial diseases. Both have been involved in studying the effects on drugs on the endocannabinoid system.

The group of Prof. Ad IJzerman & Dr. Laura Heitman aims to understand ligand-receptor interactions and thereby drug action. The group wants to use that understanding for a more rational approach of drug design and thereby improve drug candidates. For this, they pursue a ‘medicinal chemistry’ approach, in which synthetic chemistry, bio- and cheminformatics, biochemistry/molecular biology and molecular pharmacology are combined. The group is interested in so-called novel receptor concepts that might improve drug action, three of which are ‘allosteric modulation’, ‘inverse agonism’, and ‘drug-target kinetics’. These themes are applied on G protein-coupled receptors (GPCRs).

Within the Profile Programme the group works on two of these GPCRs, namely the cannabinoid receptor 1 and 2. Here the research is evolved around the concept of drug-target kinetics for two reasons: 1) to identify kinetic parameters, such as association rates and target residence times, that support the differentiation of ligands and evaluate to which extent these parameters can be exploited to predict or optimize selectivity and in vivo efficacy of ligands, and 2) to optimize probes’ binding kinetics for activity-based protein profiling (ABPP) to increase the labeling efficiency and reduce off-target labeling.

Principal investigators: 
Prof. dr. Thomas Hankemeier
Prof. dr. Piet Hein van der Graaf
Prof. dr. Ad IJzerman
Dr. Laura Heitman