Investigations of binding mode for the cyclopentapeptide CXCR4 antagonist FC131 by induced fit docking

Abstract

The GPCR CXCR4 is a chemokine receptor that by activation of its natural ligand SDF-1α is involved in the pathology of several diseases like cancer metastasis, leukemia cell progression and rheumatoid arthritis. The finding that CXCR4 plays a critical role for HIV-1 entry into T cells prompts additional motivation for the design of CXCR4 inhibitor. The establishment of the possible binding mode(s) for the cyclopentapeptide FC131 is decisive for the development of such inhibitor. Induced fit docking, which allowed flexibility for both the ligand and receptor structure, was used to generate ligand-receptor complexes. The resulting poses were compared based on their XP score and two ligand binding modes were suggested. In addition to this, mutational analysis on three CXCR4 residues which are believed to be important for HIV infection of T cells was performed.