Division of Drug Discovery & Safety
Molecular Pharmacology
In this research group, headed by Laura Heitman, novel receptor concepts in drug discovery are studied, aiming to increase the effectivity of medicines. Many drugs act via so-called G protein-coupled receptors (GPCRs) and therefore our research is mainly focused on understanding and improving drug-receptor interactions at these targets. Specifically, we focus on understanding and improving target binding kinetics and allosteric modulation of GPCRs.
Vision and ambition on the importance structure-kinetics-relationships (SKR) as a ‘translational parameter’ in early drug discovery. Understanding the SKR of a compound can result in an improved physiological effect, and thus drug candidates with improved safety and efficacy.
In 2009, the concept of ‘drug-target residence time’ or ‘drug-target kinetics’ had not received much attention, if at all. Since then it is slowly being realized that the time a drug remains bound to its target may be of greater importance for its effect in the patient than its affinity. Currently, an increased number of papers are being published that describe the importance of optimizing a drug’s binding kinetics.
However, very few really report on this novel parameter as a prospective tool, i.e., designing compounds to have optimal kinetics, rather than ‘stumbling upon’ a compound with an interesting kinetic profile. In the last couple of years we have started to publish such data and, based on the many invitations for conferences and success in getting grants approved, this work is clearly judged as being of high importance to the field.
Our expectation is that in the next 5 - 10 years, kinetic aspects of the drug-target interaction can and will routinely be studied in robust and accessible assays for all main drug target classes. Furthermore, in the future ‘kinetic’ knowledge will ultimately guide the lead finding and optimization process in the early phases of drug discovery.
Apart from studying receptor binding kinetics, we have a second, more technological, research line around ‘label-free’ (i.e., using the xCELLigence® platform) measurements of drug responses on living cells. For example, in the past five years we have worked on ‘precision medicine’ for GPCRs using the materials and genetic information from the Netherlands Twin Register (NTR) in collaboration with the VUMC and LUMC.
Moreover, this technology will be further established in research on cancer therapy using (breast) cancer cell lines and in research on cell migration and signaling upon GPCR activation or inhibition. Altogether, we envision that ‘label-free’ technology can be used for diverse applications in early drug discovery, both in fundamental and translational research.
Current research projects
- IWT-O&O “Kinetic profiling as a novel concept for GPCR drug action”
- IMI- ‘ReSOLUTE’
- ZonMW MKMB grant “Generation and characterization of conditionally immortalized cardiomyocytes: A new and versatile cell platform for cardiac disease modelling, drug screening and regenerative medicine”
- NWO-CW: ECHO-STIP “Novel target engagement biomarkers for better drug candidates”
Key publications
- Xia L., de Vries H., Yang X., Lenselink E.B., Kyrizaki A., Barth F., Louvel J., Dreyer M.K., van der Es D., IJzerman A.P., Heitman L.H., Kinetics of human cannabinoid 1 (CB1) receptor antagonists: Structure-kinetics relationships (SKR) and implications for insurmountable antagonism. Biochem Pharmacol. 2018.
- Nederpelt I., Kuzikov M., de Witte W.E.A., Schnider P., Tuijt B., Gul S., IJzerman A.P., de Lange E.C.M., Heitman L.H., From receptor binding kinetics to signal transduction; a missing link in predicting in vivo drug-action. Sci Rep. 2017, 7, 14169.
- Bot I, Ortiz Zacarias NV, de Vries H, van Santbrink PJ, van der Velden D, Kroner MJ, Kuiper J, Stamos D, IJzerman AP, Heitman LH. A novel long residence time CCR2 antagonist inhibits atherogenesis in apoE deficient mice. Scient. Rep. 2017, 7, 52.
- Soethoudt M., Grether U., Fingerle J., Grim T.W., Fezza F., de Petrocellis L., Ullmer C., Rothenhausler B., Perret C., van Gils N., Finlay D., MacDonald C., Chicca A., Gens M.D., Stuart J., de Vries H., Mastrangelo N., Xia L., Alachouzos G., Baggelaar M., Martella A., Mock E.D., Deng H., Heitman L.H., Connor M., di Marzo V., Gertsch J., Lichtman A.H., Maccarrone M., Pacher P., Glass M., van der Stelt M., Cannabinoid CB2 Receptor Ligand Profiling Reveals Biased Signaling and Off-target Activity: Implications for Drug Discovery. Nat Commun. 2017, 8, 13958.
- Zheng Y., Qin L., Zacarías N.V., de Vries H., Han G.W., Gustavsson M., Dabros M., Zhao C., Cherney R.J., Carter P., Stamos D., Abagyan R., Cherezov V., Stevens R.C., IJzerman A.P., Heitman L.H., Tebben A., Kufareva I., Handel T.M., Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature. 2016, 540, 458.