Structure-based exploration and pharmacological evaluation of N-substituted piperidin-4-yl-methanamine CXCR4 chemokine receptor antagonists

I. Adlere, S. Sun, A. Zarca, L. Roumen, M. Gozelle, C. Viciano Perpiñá, B. Caspar, M. Arimont, J. P. Bebelman, S. J. Briddon, C. Hoffmann, S. J. Hill, M. J. Smit, H. F. Vischer, M. Wijtmans, C. de Graaf, I. J.P. de Esch, R. Leurs*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

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Abstract

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.

Original languageEnglish
Pages (from-to)631-649
Number of pages19
JournalEuropean Journal of Medicinal Chemistry
Volume162
Early online date30 Oct 2018
DOIs
Publication statusPublished - 15 Jan 2019

Keywords

  • 3D-QSAR
  • Antagonists
  • CXCR4 chemokine receptor
  • G protein-coupled receptors
  • Structure-activity relationship
  • Structure-based fragment virtual screening

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