In silico guided identification of molecular determinants for modulation of CXCR4 and CXCR7

Early stage researcher 1 (ESR5) project – Marta Arimont Segura
Supervision: Dr C de Graaf, Prof IJ de Esch, Dr H Vischer, Prof MJ Smit, Prof R Leurs
Host: VU (NL) – VU University Amsterdam, Dept. of Medicinal Chemistry

I- Project proposal:

1. Develop three-dimensional molecular models to predict interaction of ligands with orthosteric and allosteric CXCR4 and CXCR7 binding sites.

2. Identify molecular determinants and unravel mechanisms of orthosteric and allosteric modulation of CXCR4 and CXCR7 function.

3. Computer-aided discovery and design of novel CXCR4 and CXCR7 modulators.

Existing and emerging GPCR structural information (including crystal structures, mutagenesis studies, fluorescent/bioluminescent/biophysical data) will be analysed and combined with GPCR ligand information (including SAR data generated in the ONCORNET program, data mining of ChEMBL) to develop molecular models for CXCR4 and CXCR7 chemokine receptors. Ligand- and structure-based models will be combined to obtain accurate ligand-receptor interaction models that can map the CXCR4 and CXCR7 binding sites and lead to a better understanding of ligand-receptor binding characteristics (e.g., affinity, activity, binding kinetics). Molecular insights will be used to perform virtual screening and computer-aided ligand optimization studies to identify and design new CXCR4 and CXCR7 ligands (in collaboration with ESR1). Planned secondments: Euroscreen (BE), Griffin Discoveries (NL).


II- Requirement candidate:

Required diploma: MSc degree in (Medicinal) Chemistry, Chem/Bioinformatics, Pharmaceutical Sciences or related Molecular Life Science degree.

Required expertise: The candidate has experience in using a wide variety of computer-aided drug design tools (protein homology modelling, pharmacophore modelling, molecular dynamics) and virtual screening protocols (e.g., molecular docking and pharmacophore screening). Recommended expertise: The candidate should have a thorough understanding in structure-activity relationships, X-ray analysis, drug design and have a basic understanding of (or interest in) synthetic organic chemistry

Key publications:
1. Scholten DJ, Roumen L, Wijtmans M, Verkade-Vreeker MC, Custers H, Lai M, de Hooge D, Canals M, de Esch IJ, Smit MJ, de Graaf C, Leurs R. (2014) Identification of overlapping but differential binding sites for the high-affinity CXCR3 antagonists NBI-74330 and VUF11211. Mol Pharmacol. 85: 116-26.

2. Istyastono, EP, Nijmeijer S, Lim HD, van de Stolpe A, Roumen L, Kooistra AJ, Vischer H, de Esch IJP, Leurs R, de Graaf C. Molecular determinants of ligand binding modes in the histamine H4 receptor: Linking ligand-based 3D-QSAR models to in silico guided receptor mutagenesis studies. J Med Chem 2011; 54: 8136-8147.

3. Sirci F, Istyastono EP, Vischer HF, Kooistra AJ, Nijmeijer S, Kuijer M, Wijtmans M, Mannhold R, Leurs R, de Esch IJ, de Graaf C. (2012) Virtual fragment screening: discovery of histamine H3 receptor ligands using ligand-based and protein-based molecular fingerprints. J Chem Inf Model. 52: 3308-24.

4. de Graaf C, Kooistra AJ, Vischer HF, Katritch V, Kuijer M, Shiroishi M, Iwata S, Shimamura T, Stevens RC, de Esch IJ, Leurs R. (2011) Crystal structure-based virtual screening for fragment-like ligands of the human histamine H(1) receptor. J Med Chem. 54: 8195-206

Follow us on

Great way to finish the week off with some #FCS measurements of CXCR4-expressing HEK cells at @UoNLifeSci 🔬 #FluorescenceFriday

Hello everyone!
I am Noemi Karsai and I’m the next in our #ESR introduction series. I’m #ESR11 and I’m originally from Hungary, currently doing my PhD at @UoNLifeSci @COMPARE_UoBUoN, UK.

The transatlantic ECI GPCR symposium #ECIGPCR is about to start, we are ready!! Thanks to the organizers for their excellent job gathering almost 500 people across the globe! @cyclic_Andreas @NicoleAPerry1 @BenderSci @DesislavaNeshe1

Hello 🙂
I am here to continue the series in which all #ESRs are presenting themselves. I am Viviana Marolda and I am in my first year of PhD. I am #ESR13, originally from Italy, and currently, I am working as a PhD student in @CBMSO_CSIC_UAM, at Universidad Autonoma de Madrid.

Hey twitter!
I am @DehanComez. I am taking over the Oncornet account for a while to start a series of all #ESRs writing about themselves and their projects. I am #ESR5, originally from Turkey and right now I am working as a PhD student in @COMPARE_UoBUoN , @UniofNottingham , UK.

New review on #gpcr structural dynamics out in COSB. Great teamwork with the @JanaSelent group. Thanks to @Lundbeckfonden and @novonordiskfond

ONCORNET2.0 is the successor to #ONCORNET. You can see some of the work of ESRs from the first ONCORNET in this special issue of @MolPharmJournal from 2019, with reviews on #CXCR4 and #ACKR3 structure and function:

Hi everyone – we’re on Twitter! ONCORNET2.0 is a #MarieCurie ITN of 16 ESRs across Europe studying #chemokine #GPCRs #CXCR4 and #ACKR3 in cancer. Our projects cover molecular dynamics, medchem, #pharmacology through to translational work. Follow us for updates from our ESRs!

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Contact details

Please contact us at:

ONCORNET Coordinator
VU University Amsterdam
The Netherlands