Rob Leurs

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Organization: Kyoto University , Belgium

Department: Department of Cell Biology

Title: Professor(PhD)

TOPICS

Organic Chemistry

Chemicals
References

The Future of Drug Development for Neglected Tropical Diseases: How the European Commission Can Continue to Make a Difference

Co-reporter:Raymond J. Pierce, Jane MacDougall, Rob Leurs, Maria Paola Costi

Trends in Parasitology 2017 Volume 33, Issue 8(Issue 8) pp:

Publication Date(Web):1 August 2017

DOI:10.1016/j.pt.2017.04.007

In this article, the four coordinators of neglected tropical disease (NTD) drug development projects funded under the European Commission (EC) Framework Programme 7 argue that the EC should reassess their funding strategy to cover the steps necessary to translate a lead compound into a drug candidate for testing in clinical trials, and suggest ways in which this might be achieved.

Identification of Ligand Binding Hot Spots of the Histamine H1 Receptor following Structure-Based Fragment Optimization

Co-reporter:Sebastiaan Kuhne, Albert J. Kooistra, Reggie Bosma, Andrea Bortolato, Maikel Wijtmans, Henry F. Vischer, Jonathan S. Mason, Chris de Graaf, Iwan J. P. de Esch, and Rob Leurs

Journal of Medicinal Chemistry 2016 Volume 59(Issue 19) pp:9047-9061

Publication Date(Web):September 19, 2016

DOI:10.1021/acs.jmedchem.6b00981

Developments in G protein-coupled receptor (GPCR) structural biology provide insights into GPCR-ligand binding. Compound 1 (4-(2-benzylphenoxy)piperidine) with high ligand efficiency for the histamine H1 receptor (H1R) was used to design derivatives to investigate the roles of (i) the amine-binding region, (ii) the upper and lower aromatic region, and (iii) binding site solvation. SAR analysis showed that the amine-binding region serves as the primary binding hot spot, preferably binding small tertiary amines. In silico prediction of water network energetics and mutagenesis studies indicated that the displacement of a water molecule from the amine-binding region is most likely responsible for the increased affinity of the N-methylated analog of 1. Deconstruction of 1 showed that the lower aromatic region serves as a secondary binding hot spot. This study demonstrates that an X-ray structure in combination with tool compounds, assessment of water energetics, and mutagenesis studies enables SAR exploration to map GPCR-ligand binding hot spots.

Discovery of Novel Trypanosoma brucei Phosphodiesterase B1 Inhibitors by Virtual Screening against the Unliganded TbrPDEB1 Crystal Structure

Co-reporter:Chimed Jansen ; Huanchen Wang ; Albert J. Kooistra ; Chris de Graaf ; Kristina M. Orrling ; Hermann Tenor ; Thomas Seebeck ; David Bailey ; Iwan J. P. de Esch ; Hengming Ke

Journal of Medicinal Chemistry 2013 Volume 56(Issue 5) pp:2087-2096

Publication Date(Web):February 14, 2013

DOI:10.1021/jm3017877

Trypanosoma brucei cyclic nucleotide phosphodiesterase B1 (TbrPDEB1) and TbrPDEB2 have recently been validated as new therapeutic targets for human African trypanosomiasis by both genetic and pharmacological means. In this study we report the crystal structure of the catalytic domain of the unliganded TbrPDEB1 and its use for the in silico screening for new TbrPDEB1 inhibitors with novel scaffolds. The TbrPDEB1 crystal structure shows the characteristic folds of human PDE enzymes but also contains the parasite-specific P-pocket found in the structures of Leishmania major PDEB1 and Trypanosoma cruzi PDEC. The unliganded TbrPDEB1 X-ray structure was subjected to a structure-based in silico screening approach that combines molecular docking simulations with a protein–ligand interaction fingerprint (IFP) scoring method. This approach identified six novel TbrPDEB1 inhibitors with IC50 values of 10–80 μM, which may be further optimized as potential selective TbrPDEB inhibitors.

Bispyrimidines as Potent Histamine H4 Receptor Ligands: Delineation of Structure–Activity Relationships and Detailed H4 Receptor Binding Mode

Co-reporter:Harald Engelhardt ; Sabine Schultes ; Chris de Graaf ; Saskia Nijmeijer ; Henry F. Vischer ; Obbe P. Zuiderveld ; Julia Dobler ; Katharina Stachurski ; Moriz Mayer ; Heribert Arnhof ; Dirk Scharn ; Eric E. J. Haaksma ; Iwan J. P. de Esch

Journal of Medicinal Chemistry 2013 Volume 56(Issue 11) pp:4264-4276

Publication Date(Web):May 13, 2013

DOI:10.1021/jm301886t

The basic methylpiperazine moiety is considered a necessary substructure for high histamine H4 receptor (H4R) affinity. This moiety is however also the metabolic hot spot for various classes of H4R ligands (e.g., indolcarboxamides and pyrimidines). We set out to investigate whether mildly basic 2-aminopyrimidines in combination with the appropriate linker can serve as a replacement for the methylpiperazine moiety. In the series of 2-aminopyrimidines, the introduction of an additional 2-aminopyrimidine moiety in combination with the appropriate linker lead to bispyrimidines displaying pKi values for binding the human H4R up to 8.2. Furthermore, the methylpiperazine replacement results in compounds with improved metabolic properties. The attempt to transfer the knowledge generated in the class of bispyrimidines to the indolecarboxamides failed. Combining the derived structure–activity relationships with homology modeling leads to new detailed insights in the molecular aspects of ligand–H4R binding in general and the binding mode of the described bispyrimidines in specific.

Design and pharmacological characterization of VUF14480, a covalent partial agonist that interacts with cysteine 983.36 of the human histamine H4 receptor

Co-reporter:S Nijmeijer;H Engelhardt;S Schultes;A C van de Stolpe;V Lusink;C de Graaf;M Wijtmans;E E J Haaksma;I J P de Esch;K Stachurski;H F Vischer;R Leurs

British Journal of Pharmacology 2013 Volume 170( Issue 1) pp:89-100

Publication Date(Web):

DOI:10.1111/bph.12113

Background and Purpose

The recently proposed binding mode of 2-aminopyrimidines to the human (h) histamine H₄ receptor suggests that the 2-amino group of these ligands interacts with glutamic acid residue E182^5.46 in the transmembrane (TM) helix 5 of this receptor. Interestingly, substituents at the 2-position of this pyrimidine are also in close proximity to the cysteine residue C98^3.36 in TM3. We hypothesized that an ethenyl group at this position will form a covalent bond with C98^3.36 by functioning as a Michael acceptor. A covalent pyrimidine analogue will not only prove this proposed binding mode, but will also provide a valuable tool for H₄ receptor research.

Experimental Approach

We designed and synthesized VUF14480, and pharmacologically characterized this compound in hH₄ receptor radioligand binding, G protein activation and β-arrestin2 recruitment experiments. The ability of VUF14480 to act as a covalent binder was assessed both chemically and pharmacologically.

Key Results

VUF14480 was shown to be a partial agonist of hH₄ receptor-mediated G protein signalling and β-arrestin2 recruitment. VUF14480 bound covalently to the hH₄ receptor with submicromolar affinity. Serine substitution of C98^3.36 prevented this covalent interaction.

Conclusion and Implications

VUF14480 is thought to bind covalently to the hH₄ receptor-C98^3.36 residue and partially induce hH₄ receptor-mediated G protein activation and β-arrestin2 recruitment. Moreover, these observations confirm our previously proposed binding mode of 2-aminopyrimidines. VUF14480 will be a useful tool to stabilize the receptor into an active confirmation and further investigate the structure of the active hH₄ receptor.

Linked Articles

This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/ 10.1111/bph.2013.170.issue-1

Detailed analysis of biased histamine H4 receptor signalling by JNJ 7777120 analogues

Co-reporter:S Nijmeijer;H F Vischer;F Sirci;S Schultes;H Engelhardt;C de Graaf;E M Rosethorne;S J Charlton;R Leurs

British Journal of Pharmacology 2013 Volume 170( Issue 1) pp:78-88

Publication Date(Web):

DOI:10.1111/bph.12117

Background and Purpose

The histamine H₄ receptor, originally thought to signal merely through Gα_i proteins, has recently been shown to also recruit and signal via β-arrestin2. Following the discovery that the reference antagonist indolecarboxamide JNJ 7777120 appears to be a partial agonist in β-arrestin2 recruitment, we have identified additional biased hH₄R ligands that preferentially couple to Gα_i or β-arrestin2 proteins. In this study, we explored ligand and receptor regions that are important for biased hH₄R signalling.

Experimental Approach

We evaluated a series of 48 indolecarboxamides with subtle structural differences for their ability to induce hH₄R-mediated Gα_i protein signalling or β-arrestin2 recruitment. Subsequently, a Fingerprints for Ligands and Proteins three-dimensional quantitative structure–activity relationship analysis correlated intrinsic activity values with structural ligand requirements. Moreover, a hH₄R homology model was used to identify receptor regions important for biased hH₄R signalling.

Key Results

One indolecarboxamide (75) with a nitro substituent on position R7 of the aromatic ring displayed an equal preference for the Gα_i and β-arrestin2 pathway and was classified as unbiased hH₄R ligand. The other 47 indolecarboxamides were β-arrestin2-biased agonists. Intrinsic activities of the unbiased as well as β-arrestin2-biased indolecarboxamides to induce β-arrestin2 recruitment could be correlated with different ligand features and hH₄R regions.

Conclusion and Implications

Small structural modifications resulted in diverse intrinsic activities for unbiased (75) and β-arrestin2-biased indolecarboxamides. Analysis of ligand and receptor features revealed efficacy hotspots responsible for biased-β-arrestin2 recruitment. This knowledge is useful for the design of hH₄R ligands with biased intrinsic activities and aids our understanding of the mechanism of H₄R activation.

Linked Articles

This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/ 10.1111/bph.2013.170.issue-1

Catechol Pyrazolinones as Trypanocidals: Fragment-Based Design, Synthesis, and Pharmacological Evaluation of Nanomolar Inhibitors of Trypanosomal Phosphodiesterase B1

Co-reporter:Kristina M. Orrling ; Chimed Jansen ; Xuan Lan Vu ; Vreni Balmer ; Patrick Bregy ; Anitha Shanmugham ; Paul England ; David Bailey ; Paul Cos ; Louis Maes ; Emily Adams ; Erika van den Bogaart ; Eric Chatelain ∞; Jean-Robert Ioset ∞; Andrea van de Stolpe ; Stèphanie Zorg ; Johan Veerman ×; Thomas Seebeck ; Geert Jan Sterk ×; Iwan J. P. de Esch

Journal of Medicinal Chemistry 2012 Volume 55(Issue 20) pp:8745-8756

Publication Date(Web):September 10, 2012

DOI:10.1021/jm301059b

Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei, the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. We used homology modeling and docking studies to guide fragment growing into the parasite-specific P-pocket in the enzyme binding site. The resulting catechol pyrazolinones act as potent TbrPDEB1 inhibitors with IC50 values down to 49 nM. The compounds also block parasite proliferation (e.g., VUF13525 (20b): T. brucei rhodesiense IC50 = 60 nM, T. brucei brucei IC50 = 520 nM, T. cruzi = 7.6 μM), inducing a typical multiple nuclei and kinetoplast phenotype without being generally cytotoxic. The mode of action of 20b was investigated with recombinantly engineered trypanosomes expressing a cAMP-sensitive FRET sensor, confirming a dose-response related increase of intracellular cAMP levels in trypanosomes. Our findings further validate the TbrPDEB family as antitrypanosomal target.

Chemical Subtleties in Small-Molecule Modulation of Peptide Receptor Function: The Case of CXCR3 Biaryl-Type Ligands

Co-reporter:Maikel Wijtmans ; Danny J. Scholten ; Luc Roumen ; Meritxell Canals ; Hans Custers ; Marjolein Glas ; Marlies C. A. Vreeker ; Frans J. J. de Kanter ; Chris de Graaf ; Martine J. Smit ; Iwan J. P. de Esch

Journal of Medicinal Chemistry 2012 Volume 55(Issue 23) pp:10572-10583

Publication Date(Web):November 14, 2012

DOI:10.1021/jm301240t

The G protein-coupled chemokine receptor CXCR3 plays a role in numerous inflammatory events. The endogenous ligands for the chemokine receptors are peptides, but in this study we disclose small-molecule ligands that are able to activate CXCR3. A class of biaryl-type compounds that is assembled by convenient synthetic routes is described as a new class of CXCR3 agonists. Intriguingly, structure–activity relationship and structure–function relationship studies reveal that subtle chemical modifications on the outer aryl ring (e.g., either the size or position of a halogen atom) result in a full spectrum of agonist efficacies on CXCR3. Quantum mechanics calculations and nuclear Overhauser effect spectroscopy NMR studies suggest that the biaryl dihedral angle and the electronic nature of ortho-substituents play an important role in determining agonist efficacies. Compounds 38 (VUF11222) and 39 (VUF11418) are the first reported nonpeptidomimetic agonists on CXCR3, rendering them highly useful chemical tools for detailed assessment of CXCR3 activation as well as for studying downstream CXCR3 signaling.

Pharmacological modulation of chemokine receptor function

Co-reporter:DJ Scholten;M Canals;D Maussang;L Roumen;MJ Smit;M Wijtmans;C de Graaf;HF Vischer ;R Leurs

British Journal of Pharmacology 2012 Volume 165( Issue 6) pp:1617-1643

Publication Date(Web):

DOI:10.1111/j.1476-5381.2011.01551.x

G protein-coupled chemokine receptors and their peptidergic ligands are interesting therapeutic targets due to their involvement in various immune-related diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease, HIV-1 infection and cancer. To tackle these diseases, a lot of effort has been focused on discovery and development of small-molecule chemokine receptor antagonists. This has been rewarded by the market approval of two novel chemokine receptor inhibitors, AMD3100 (CXCR4) and Maraviroc (CCR5) for stem cell mobilization and treatment of HIV-1 infection respectively. The recent GPCR crystal structures together with mutagenesis and pharmacological studies have aided in understanding how small-molecule ligands interact with chemokine receptors. Many of these ligands display behaviour deviating from simple competition and do not interact with the chemokine binding site, providing evidence for an allosteric mode of action. This review aims to give an overview of the evidence supporting modulation of this intriguing receptor family by a range of ligands, including small molecules, peptides and antibodies. Moreover, the computer-assisted modelling of chemokine receptor–ligand interactions is discussed in view of GPCR crystal structures. Finally, the implications of concepts such as functional selectivity and chemokine receptor dimerization are considered.

LINKED ARTICLES This article is part of a themed section on the Molecular Pharmacology of G Protein-Coupled Receptors (GPCRs). To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-6. To view the 2010 themed section on the same topic visit http://onlinelibrary.wiley.com/doi/10.1111/bph.2010.159.issue-5/issuetoc

Pharmacological characterization of a small-molecule agonist for the chemokine receptor CXCR3

Co-reporter:DJ Scholten;M Canals;M Wijtmans;S de Munnik;P Nguyen;D Verzijl;IJP de Esch;HF Vischer;MJ Smit ;R Leurs

British Journal of Pharmacology 2012 Volume 166( Issue 3) pp:898-911

Publication Date(Web):

DOI:10.1111/j.1476-5381.2011.01648.x

BACKGROUND AND PURPOSE

The chemokine receptor CXCR3 is a GPCR found predominantly on activated T cells. CXCR3 is activated by three endogenous peptides; CXCL9, CXCL10 and CXCL11. Recently, a small-molecule agonist, VUF10661, has been reported in the literature and synthesized in our laboratory. The aim of the present study was to provide a detailed pharmacological characterization of VUF10661 by comparing its effects with those of CXCL11.

EXPERIMENTAL APPROACH

Agonistic properties of VUF10661 were assessed in a chemotaxis assay with murine L1.2 cells transiently transfected with cDNA encoding the human CXCR3 receptor and in binding studies, with [¹²⁵I]-CXCL10 and [¹²⁵I]-CXCL11, on membrane preparations from HEK293 cells stably expressing CXCR3. [³⁵S]-GTPγS binding was used to determine its potency to induce CXCR3-mediated G protein activation and BRET-based assays to investigate its effects on intracellular cAMP levels and β-arrestin recruitment.

KEY RESULTS

VUF10661 acted as a partial agonist in CXCR3-mediated chemotaxis, bound to CXCR3 in an allosteric fashion in ligand binding assays and activated G_i proteins with the same efficacy as CXCL11 in the [³⁵S]-GTPγS binding and cAMP assay, while it recruited more β-arrestin1 and β-arrestin2 to CXCR3 receptors than the chemokine.

CONCLUSIONS AND IMPLICATIONS

VUF10661, like CXCL11, activates both G protein-dependent and -independent signalling via the CXCR3 receptor, but probably exerts its effects from an allosteric binding site that is different from that for CXCL11. It could stabilize different receptor and/or β-arrestin conformations leading to differences in functional output. Such ligand-biased signalling might offer interesting options for the therapeutic use of CXCR3 agonists.

LINKED ARTICLE

This article is commented on by O'Boyle, pp. 895–897 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01759.x

Synthesis, modeling and functional activity of substituted styrene-amides as small-molecule CXCR7 agonists

Co-reporter:Maikel Wijtmans, David Maussang, Francesco Sirci, Danny J. Scholten, Meritxell Canals, Azra Mujić-Delić, Milagros Chong, Kristell L.S. Chatalic, Hans Custers, Elwin Janssen, Chris de Graaf, Martine J. Smit, Iwan J.P. de Esch, Rob Leurs

European Journal of Medicinal Chemistry 2012 Volume 51() pp:184-192

Publication Date(Web):May 2012

DOI:10.1016/j.ejmech.2012.02.041

The chemokine receptor CXCR7 is an atypical G protein-coupled receptor as it preferentially signals through the β-arrestin pathway rather than through G proteins. CXCR7 is thought to be of importance in cancer and the development of CXCR7-targeting ligands is of huge importance to further elucidate the pharmacology and the therapeutic potential of CXCR7. In the present study, we synthesized 24 derivatives based on a compound scaffold patented by Chemocentryx and obtained CXCR7 ligands with pKi values ranging from 5.3 to 8.1. SAR studies were supported by computational 3D Fingerprint studies, revealing several important affinity descriptors. Two key compounds (29 and 30, VUF11207 and VUF11403) were found to be high-potency ligands that induce recruitment of β-arrestin2 and subsequent internalization of CXCR7, making them important tool compounds in future CXCR7 research.Highlights► Substituted styrene-amides are excellent CXCR7 binders. ► Computational model suggests important molecular descriptors. ► Key compounds induce recruitment of β-arrestin2 to CXCR7. ► Key compounds induce CXCR7 internalization.

Detailed structure–activity relationship of indolecarboxamides as H4 receptor ligands

Co-reporter:Harald Engelhardt, Iwan J.P. de Esch, Daniel Kuhn, Rogier A. Smits, Obbe P. Zuiderveld, Julia Dobler, Moriz Mayer, Sebastian Lips, Heribert Arnhof, Dirk Scharn, Eric E.J. Haaksma, Rob Leurs

European Journal of Medicinal Chemistry 2012 Volume 54() pp:660-668

Publication Date(Web):August 2012

DOI:10.1016/j.ejmech.2012.06.016

A series of 76 derivatives of the indolecarboxamide 1 were synthesized, which allows a detailed SAR investigation of this well known scaffold. The data enable the definition of a predictive QSAR model which identifies several compounds with an activity comparable to 1. A selection of these new H4R antagonists was synthesized and a comparison of predicted and measured values demonstrates the robustness of the model (47–55). In addition to the H4-receptor activity general CMC and DMPK properties were investigated. Some of the new analogs are not only excellently soluble, but display a significantly increased half-life in mouse liver microsomes as well. These properties qualify these compounds as a possible new standard for future in vivo studies (e.g 51, 52 and 55). Moreover, the current studies also provide valuable information on the potential receptor ligand interactions between the indolcarboxamides and the H4R protein.Graphical abstractHighlights► Comprehensive SAR for H4R affinity around the indolecarboxamide scaffold. ► Predictive Free-Wilson QSAR model established. ► Identification of microsomal stable indolecarboxamide derivatives.

Ligand based design of novel histamine H4 receptor antagonists; fragment optimization and analysis of binding kinetics

Co-reporter:Rogier A. Smits, Herman D. Lim, Tiffany van der Meer, Sebastiaan Kuhne, Karin Bessembinder, Obbe P. Zuiderveld, Maikel Wijtmans, Iwan J.P. de Esch, Rob Leurs

Bioorganic & Medicinal Chemistry Letters 2012 Volume 22(Issue 1) pp:461-467

Publication Date(Web):1 January 2012

DOI:10.1016/j.bmcl.2011.10.104

The histamine H4 receptor is a G protein-coupled receptor that has attracted much interest for its role in inflammatory and immunomodulatory functions. In our search for new H4R ligands, a low affinity isoquinoline fragment was optimized to 7-(furan-2-yl)-4-(piperazin-1-yl)quinazolin-2-amine (VUF11489), as a new H4R antagonist. Analysis of its binding kinetics at the human H4R showed this compound to have a very different dissociative half-life in comparison with reference antagonist JNJ7777120.

Crystal Structure-Based Virtual Screening for Fragment-like Ligands of the Human Histamine H1 Receptor

Co-reporter:Chris de Graaf ; Albert J. Kooistra ; Henry F. Vischer ; Vsevolod Katritch ; Martien Kuijer ; Mitsunori Shiroishi ; So Iwata ×; Tatsuro Shimamura ×; Raymond C. Stevens ; Iwan J. P. de Esch

Journal of Medicinal Chemistry 2011 Volume 54(Issue 23) pp:8195-8206

Publication Date(Web):October 18, 2011

DOI:10.1021/jm2011589

The recent crystal structure determinations of druggable class A G protein-coupled receptors (GPCRs) have opened up excellent opportunities in structure-based ligand discovery for this pharmaceutically important protein family. We have developed and validated a customized structure-based virtual fragment screening protocol against the recently determined human histamine H1 receptor (H1R) crystal structure. The method combines molecular docking simulations with a protein–ligand interaction fingerprint (IFP) scoring method. The optimized in silico screening approach was successfully applied to identify a chemically diverse set of novel fragment-like (≤22 heavy atoms) H1R ligands with an exceptionally high hit rate of 73%. Of the 26 tested fragments, 19 compounds had affinities ranging from 10 μM to 6 nM. The current study shows the potential of in silico screening against GPCR crystal structures to explore novel, fragment-like GPCR ligand space.

En route to new blockbuster anti-histamines: surveying the offspring of the expanding histamine receptor family

Co-reporter:Rob Leurs, Henry F. Vischer, Maikel Wijtmans, Iwan J.P. de Esch

Trends in Pharmacological Sciences (April 2011) Volume 32(Issue 4) pp:250-257

Publication Date(Web):1 April 2011

DOI:10.1016/j.tips.2011.02.004

With the recognition of two new histamine receptors at the start of the new millennium, the field of histamine research has seen a clear revival. In the last 10 years, many academic and industrial groups have taken up the challenge to target these new members of the aminergic G-protein-coupled receptor (GPCR) family. Histamine receptor research nicely illustrates how GPCR research has changed in the post-genomic era. There is a growing understanding of GPCR structure, function and modulation at a molecular level. Emerging concepts such as receptor isoforms, GPCR oligomerization and ligand-biased signaling are all being studied, but their clinical relevance remains to be determined. The histamine H3 and H4 drug development programs can help to establish the link between these molecular features and clinical efficacy. Several new anti-histamines are now being tested for diverse clinical applications and are poised to become the next blockbuster drugs targeting histamine receptors.