Probing the molecular interactions between CXC chemokine receptor 4 (CXCR4) and an arginine-based tripeptidomimetic antagonist (KRH-1636)

Abstract

We here report an experimentally verified binding mode for the known tripeptidomimetic CXCR4 antagonist KRH-1636 (1). A limited SAR study based on the three functionalities of 1 was first conducted, followed by site-directed mutagenesis studies. The receptor mapping showed that both the potency and affinity of 1 were dependent on the transmembrane residues His113, Asp171, Asp262, and His281 and also suggested the involvement of Tyr45 and Gln200 (potency) and Tyr116 and Glu288 (affinity). Molecular docking of 1 to an X-ray structure of CXCR4 showed that the l-Arg guanidino group of 1 forms polar interactions with His113 and Asp171 and the (pyridin-2-ylmethyl)amino moiety is anchored by Asp262 and His281, whereas the naphthalene ring is tightly packed in a hydrophobic subpocket formed by the aromatic side chains of Trp94, Tyr45, and Tyr116. The detailed picture of ligand–receptor interactions provided here will assist in structure-based design and further development of small-molecule peptidomimetic CXCR4 antagonists.