The department
The department of Pharmacochemistry of the Vrije Universiteit Amsterdam finds its roots in the pioneering work of Wijbe Th. Nauta, one of the founding fathers of the EFMC. In the years immediately after World War II he realized that a new chemical discipline had emerged, Medicinal Chemistry, in which especially organic chemistry was to a certain extent blended with sub disciplines from the biological and medical sciences. Nauta preferred the term Pharmacochemistry over Medicinal Chemistry, as he felt a chemist works with compounds (pharmacons) and not with medicines (tablets, pills etc.). Nauta’s chair was within the School of Chemistry and the current department is now member of the Division Chemistry and Pharmaceutical Sciences of the Faculty of Sciences. After Nauta’s retirement in 1979 he was succeeded by his student Henk Timmerman, who retired in 2002 to have his student Rob Leurs as his successor.
Rob Leurs continues to work along the original lines of the department. The mission is to produce and deliver new scientists and new science in the field of Medicinal Chemistry.
Medicinal Chemistry is defined as the branch of chemistry which focuses on the design and synthesis of new compounds, having a set of wanted - in the absence of unwanted- properties on the basis of the understanding of relationships between structure and biological activity.
For this purpose the study of the mechanisms of action at the molecular level is of prime importance. Historically, this meant that the department has not only groups for synthesis and modeling (strongly promoted by Timmerman in the 80s), but also for (molecular) pharmacology and since the late 90s especially molecular biology.
Currently there is a strong focus on relationships between receptor structure and function and (target) structure-based drug design methodologies. Moreover, as the study of mechanisms behind unwanted effects are considered to be of comparable importance, a separate chair for “Molecular Toxicology” was installed in 1985 (Prof. Dr Nico Vermeulen).
In the early 1990s the department became a partner of the Leiden-Amsterdam Center for Drug Research (LACDR), a center which comprises virtually all pharmaceutical subdisciplines, without having the task to raise new officine pharmacists. In 2006, the department took the initiative to organize relevant drug discovery activities in the faculties of Science and Earth and Life Sciences in a new VU-Drug Discovery Center in order to stimulate new multi-disciplinary research projects.
Head of the group
Professor Rob Leurs (1964) studied Pharmacochemistry at the Vrije Universiteit in Amsterdam and received his Ph.D in 1991 studying histamine receptors and ligands. From 1991 to 1993 he was a post-doc in Paris (Jean Charles Schwartz at INSERM) were he was involved in cloning the genes encoding histaminergic and serotonergic receptors. Back at his alma mater he received a prestigious 5 years fellowship of the Royal Netherlands Academy of Arts and Sciences to start his own research team. In 2002 he succeeded Henk Timmerman.
From 2003 to 2005 he was a director of the LACDR, whereas he is now director of the VU Drug Discovery Center. In 2006 he was head of the department of Chemistry & Pharmaceutical Sciences and since 2007 he is vice-Dean of the Faculty of Sciences. He is also a member of the Executive Board of the newly started (2006) Dutch Top Institute Pharma and since 2003 chairman of the Section Medicinal Chemistry of the Netherlands Organization of Science-Chemical Sciences.
As honors Rob Leurs received the Dutch Galenus Research Award (1997), the Organon Award for Pharmacology (2001), a Pfizer Academic Award (2001) and as a major grant, a Dutch “Pioneer grant”.
He is (co-) author of more than 150 papers and about 40 book chapters and has edited two books on histamine receptors and ligands.
Research Focus
The group intends to perform cutting-edge research on the molecular aspects of membrane-bound receptors, focusing on G-protein coupled receptors (GPCRs) and Ligand-Gated Ion channels (LGICs), aimed to understand the molecular interactions between the biologically active small ligands and their membrane bound protein targets and cellular signal transduction machinery. Research is an active interplay between synthetic organic chemistry, computational medicinal chemistry, molecular pharmacology and receptor biochemistry. Receptors of interest are various members of the G-protein coupled receptors for histamine (H1-H4) and chemokines (e.g. CXCR2, CXCR3, CXCR4 and viral chemokine receptors US28, BILF-1) and the nicotine LGIC receptors.
There is a close cooperation with the chairs of Molecular Toxicology (Nico Vermeulen) and Biomolecular Analysis (Hubertus Irth) and the Radionuclides Center of the Vrije Universiteit which includes a PET- Center (Bert Windhorst).
Key discoveries of the department
During the early years of the department ( “Nauta era”) the group has identified several diphenhydramine derivatives which were introduced as medicines (e.g. orphenadrine for treating parkinsonism). More recently, several new histamine ligands have been developed as research tools and are made available through commercial vendors; examples are the selective H2 receptor agonist amthamine, several H3 receptor ligands as the agonists immepip, imetit, immethridine, the antagonist clobenpropit and the radioactive H3 radioligand iodophenpropit and very recently selective ligands for the H4 receptor (e.g. VUF8430).
Other important contributions have been the finding that most of the therapeutically used H1 and H2 as antagonist are in reality inverse agonist, and, together with colleagues from Spain, the –at least in part – unravelling of the mechanism of H1 receptor activation. These computational and mutagenesis studies are currently supported by solid-state NMR measurement of histamine bound to purified H1 receptors.
The detection of constitutive active, herpesvirus encoded GPCR’s, which were subsequently found to be targets for specific chemokines, constitutes another recent success of the department. The HCMV encoded GPCR US28 is shown to be involved in tumor formation and selective inverse agonists have in the mean time been developed by the group.
Teaching
The department is responsible for a bachelors program in Pharmacochemistry (3 years) and offers a Master Program Drug Discovery & Safety with different specializations within the area of Drug Discovery (2 years). The group is also involved in the bachelor programs in Chemisty, Medical Natural Sciences and the new bachelor Science, Business and Innovation.
People
Rob Leurs is head of the department and runs together with Prof. Dr Martine Smit (full chair Receptors & cellular communication) and assistant professors Dr. Marco Siderius (Molecular Biology & biochemistry) and Dr. Iwan de Esch (modeling and synthesis) research programs on histamine, chemokine and nicotine receptors.
Prof. Dr Eric Haaksma (Boehringer Ingelheim,Vienna, Austria) holds a part-time chair in Receptor Pharmacochemistry, whereas em. Professor Henk Timmerman associates with the team.
Currently six postdocs , seven laboratory assistants(“technicians”) and over ten Ph.D. students complete the team.
Collaborations
- Dr. R. Booth (Gainsville, USA): Ligand-selective GPCR activation
- Dr. G. Van Dongen (Amsterdam, the Netherlands): oncogenesis and GPCRs
- Dr. H. De Groot/Dr. W. De Grip (Leiden, the Netherlands): GPCR purification and ssNMR
- Dr. S. Lira (New York, USA): transgenic models for (viral) chemokine receptors
- Dr. L. Pardo (Barcelona, Spain): GPCR modelling and activation
- Dr. G. Siegal (Leiden, the Netherlands): NMR screening
- Dr. A. Smit/Dr. T. Sixma (Amsterdam, the Netherlands): X-ray & mutagensis LGICs
Selected publications
- Smit MJ, Vischer HF, Bakker RA, Jongejan A, Timmerman H, Pardo L, Leurs R
Pharmacogenomic and Structural Analysis of Constitutive G Protein-Coupled Receptor Activity. - Annu Rev Pharmacol Toxicol, (2007) 47 pp.:53-87
- Ratnala VRP, Kiihne S, Buda F, Leurs R, de Groot HJM, DeGrip WJ SSNMR
Evidence for a Protonation Switch in the Binding Pocket of the H1 Receptor upon Binding of the Agonist Histamine - J Am Chem Soc, (2007) 129 pp.:867-872
- Lim HD, Smits RA, Bakker RA, van Dam CME, de Esch IJP, Leurs R
Discovery of S-(2-Guanidylethyl)-isothiourea (VUF 8430) as a Potent Nonimidazole Histamine H4 Receptor Agonist - J Med Chem, (2006) 49 pp.:6650-6651
- Maussang D, Verzijl D, van Walsum M, Leurs R, Holl J, Pleskoff O, Michel D, van Dongen GAMS, Smit MJ
Human cytomegalovirus-encded chemokine receptor US28 promotes tumorigenesis - PNAS, (2006) 103 pp.: 13068-13073
- Leurs R, Bakker RA, Timmerman H, de Esch IJP
The histamine H3 receptor: from gene cloning to H3 receptor drugs. - Nature Rev. Drug Disc, 4 (2005) pp.:107-120.
- Jongejan A, Bruysters M, Ballesteros JA, Haaksma E, Bakker RA, Pardo L, Leurs R
Linking agonist binding to histamine H1 receptor activation - Nat Chem Biol, (2005) 1 pp.:98-105
Information and contact
http://www.chem.vu.nl/en/sec/far/Medchem/frame.html
e-mail: r.leurs@few.vu.nl
By Kristian Stromgaard
