Computer-Aided Design of Peptidomimetic Antagonists of the CXCR4 Chemokine Receptor, a Therapeutic Target for Oncology and AIDS

The G-protein coupled chemokine receptor CXCR4 is a biological target of medical significance both in oncology and infectious diseases since CXCR4 activation – among other things – is associated with tumor vascularization and metastasis. In addition, the CXCR4 receptor is expressed on CD4+ T-cells and serves as the HIV entry point in AIDS. Therefore, CXCR4 antagonists (inhibitors) have great potential as drugs, more specifically as antivirals (AIDS therapy) and in the treatment of various types of cancer. However, as for other human GPCRs, the exact structure of the CXCR4 receptor is unknown, meaning that ligand-based design is crucial for the development of such antagonists. To maximize the informational content and speed of this drug design strategy (an d hence, the chance of success), it is advantageous to focus on ligands with limited conformational freedom, i.e. compounds that only can adopt a limited number of 3D shapes. Accordingly, the foundation of this project is the design of a library of semi-r igid compounds, which will be synthesized by combinatorial chemistry and tested for CXCR4 affinity in order to deduce the 3D structure of the complementary receptor-binding site. In parallel, the target receptor structure will be modeled based on homolog y to bovine rhodopsin and refined based on experimental results. Subsequent development of a reliable method for computer-based affinity prediction of CXCR4-ligands will warrant virtual screening of ligands. Synthesis and testing of the most promising com pounds from virtual screening, followed by pharmacophore refinement and lead optimization in an iterative fashion is ultimately expected to result in the development of a clinically useful CXCR4 antagonist.