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
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