(133f) Molecular Dynamics Insights Into Targeting CXCR4 By Branched Peptides Based On DV3
Chemokine Receptor Type 4 (CXCR4) is an emerging target in the development of cancer and HIV-1 drugs due to its co-receptor involvement in the migration of cancer cells and its key role in HIV-1 entry. Extensive investigations led to the discovery of an inverso antagonist peptide, DV3  derived from the sequence of a natural CXCR4 ligand, the viral macrophage-inflammatory protein - II. Recent-unpublished experiments investigated peptides incorporating 1, 2 and 4 DV3 sequences branched off a core structure consisting of 1, 2 and 4 D-lysine(s) respectively and showed that the largest ligand candidate bearing four peptides (4DV3) possesses remarkable avidity to the CXCR4 receptor, blocking HIV-1 entry in a fusion-specific antiretroviral assay. We computationally modeled the structures for the 2DV3 : CXCR4 and 4DV3 : CXCR4 complexes, which include two types of non-identical asymmetrical binding pockets to accommodate the dimer and tetramer DV3 peptide ligands, respectively, and performed extensive molecular dynamics (MD) simulations of the determined dimeric and tetrameric complexes verifying the complexes’ structural integrity. Analysis of the MD trajectories reveals the key interacting residues within the complexes, as well as peptide residues with potential for further optimization. In addition, we provide evidence on the antagonistic, anti HIV-1, role of DV3-based compounds against V3 loop binding, by comparing the present results with recent-unpublished insights from a computationally derived V3 loop : CXCR4 complex structure.
 N. Zhou et al. Exploring the Stereochemistry of CXCR4-Peptide Recognition and Inhibiting HIV-1 Entry with D-Peptides Derived from Chemokines. Journal of Biological Chemistry, 2002, 277, 17476-17485.