Q1 · MEDICINE
Article
Author: Adlere, I. ; Sun, S. ; Zarca, A. ; Roumen, L. ; Gozelle, M. ; Viciano Perpina, C. ; Caspar, B. ; Arimont, M. ; Bebelman, J. P. ; Briddon, S. J. ; Hoffmann, C. ; Hill, S. J. ; Smit, M. J. ; Vischer, H. F. ; Wijtmans, M. ; de Graaf, C. ; de Esch, I. J. P. ; Leurs, R.
Using the available structural information of the chemokine receptor CXCR4, we present hit finding and hit exploration studies that make use of virtual fragment screening, design, synthesis and structure-activity relationship (SAR) studies. Fragment 2 was identified as virtual screening hit and used as a starting point for the exploration of 31 N-substituted piperidin-4-yl-methanamine derivatives to investigate and improve the interactions with the CXCR4 binding site. Additionally, subtle structural ligand changes lead to distinct interactions with CXCR4 resulting in a full to partial displacement of CXCL12 binding and competitive and/or non-competitive antagonism. Three-dimensional quantitative structure-activity relationship (3D-QSAR) and binding model studies were used to identify important hydrophobic interactions that determine binding affinity and indicate key ligand-receptor interactions.