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

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Adlere I., Sun S., Zarca A., Roumen L., Gözelle M., Viciano C. P., ...More

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol.162, pp.631-649, 2019 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 162
  • Publication Date: 2019
  • Doi Number: 10.1016/j.ejmech.2018.10.060
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.631-649
  • Keywords: G protein-coupled receptors, CXCR4 chemokine receptor, Antagonists, Structure-based fragment virtual screening, Structure-activity relationship, 3D-QSAR, FRAGMENT-LIKE LIGANDS, HISTAMINE H-4, MOLECULAR INTERACTION, CRYSTAL-STRUCTURE, HIV ENTRY, IN-VITRO, DISCOVERY, BINDING, INHIBITION, DOCKING
  • Gazi University Affiliated: Yes


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. (C) 2018 Elsevier Masson SAS. All rights reserved.