Insight into the binding mode for cyclopentapeptide antagonists of the CXCR4 receptor

The finding that the chemokine receptor CXCR4 is involved in T-cell HIV entry has encouraged the development of antiretroviral drugs targeting this receptor. Additional evidence that CXCR4 plays a crucial role in both angiogenesis and metastasis provides further motivation for the development of a CXCR4 inhibitor for therapeutic applications in oncology. To facilitate the design of such ligands, we have investigated the possible binding modes for cyclopentapeptide CXCR4 antagonists by docking 11 high/medium affinity cyclopentapeptides to a developed three-dimensional model of the CXCR4 G-protein-coupled receptor's transmembrane region. These ligands, expected to bind in the same mode to the receptor, were docked in the previously deduced receptor-bound conformation [Vabeno et al., in press; doi 10.1002/bip.20508]. Ligand-receptor complexes were generated using an automated docking procedure that allowed ligand flexibility. By comparing the resulting ligand poses, only two binding modes common for all 11 compounds were identified. Inspection of these two ligand-receptor complexes identified several CXCR4 contact residues shown by mutation to be interaction sites for ligands and important for HIV gp120 binding. Thus, the results provide further insight into the mechanism by which these cyclopentapeptides block HIV entry as well as a basis for rational design of CXCR4 mutants to map potential contacts with small peptide ligands.