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

Research output: Contribution to JournalArticleAcademicpeer-review

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
DOIs
Publication statusPublished - 15 Jan 2019

Fingerprint

CXCR4 Receptors
Quantitative Structure-Activity Relationship
Chemokine Receptors
Screening
Pharmacology
Ligands
Competitive Binding
Structure-Activity Relationship
Hydrophobic and Hydrophilic Interactions
Binding Sites
Derivatives
methylamine

Keywords

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

Cite this

Adlere, I. ; Sun, S. ; Zarca, A. ; Roumen, L. ; Gozelle, M. ; Viciano Perpiñá, 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. / Structure-based exploration and pharmacological evaluation of N-substituted piperidin-4-yl-methanamine CXCR4 chemokine receptor antagonists. In: European Journal of Medicinal Chemistry. 2019 ; Vol. 162. pp. 631-649.
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Structure-based exploration and pharmacological evaluation of N-substituted piperidin-4-yl-methanamine CXCR4 chemokine receptor antagonists. / Adlere, I.; Sun, S.; Zarca, A.; Roumen, L.; Gozelle, M.; Viciano Perpiñá, 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.

In: European Journal of Medicinal Chemistry, Vol. 162, 15.01.2019, p. 631-649.

Research output: Contribution to JournalArticleAcademicpeer-review

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AU - Gozelle, M.

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AU - Smit, M. J.

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AU - de Esch, I. J.P.

AU - Leurs, R.

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