Discovery of CCR7 small molecule inhibitors by virtual screening andhit-to-lead optimization.

G protein-coupled receptors (GPCRs) are well-validated drug targets, with one-third of all marketed drugs acting on GPCRs. Although ~ 800 human GPCRs exist, only ~100 of them are currently being targeted in late stage preclinical development. The human chemokine receptor CCR7 is an example of a GPCR that is highly underexplored in drug discovery. CCR7 is crucial for lymphoid organogenesis and recruitment of naïve T-lymphocytes and activated dendritic cells into the lymph node, where they initiate immune responses. Despite the fact that CCR7 is implicated in a variety of human diseases (e.g., immunological disorders, inflammatory diseases, cancer), no potent and selective CCR7 small molecule ligands are available today. In this project, we will embark on different strategies to discover novel CCR7 ligands. Besides screening of small molecule compound libraries as potential CCR7 ligands, we will also engage in a computational-driven ligand- and structure-based virtual screening campaign. In addition, small molecules that have previously been described as putative CCR7 interactors, will be further optimized for increased binding affinity and selectivity, as well as for drug-like properties. The integration of these different approaches will ultimately result in the identification of novel CCR7 ligands. The best-in-class molecules will also be further evaluated in a panel of biological assays to confirm their capabililty to modulate CCR7 function in vitro. For instance, we aim to demonstrate the molecule’s capability to modulate CCR7-dependent migration of cancer cells or primary cells. Taken together, this project should be an important first step towards the discovery of novel CCR7 ligands with potential therapeutic value.

Keywords:CCR7, virtual screening, GPCR, drug discovery, hit-to-lead optimization

Disciplines:Virology