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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, C. Perpiñá; 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.

Authors

I. Adlere

S. Sun

A. Zarca

L. Roumen

M. Gozelle

C. Perpiñá Viciano

B. Caspar

M. Arimont

J.P. Bebelman

C. Hoffmann

STEPHEN HILL steve.hill@nottingham.ac.uk
Professor of Molecular Pharmacology

M.J. Smit

H.F. Vischer

M. Wijtmans

C. de Graaf

I.J.P. de Esch

R. Leurs



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.

Journal Article Type Article
Publication Date Jan 15, 2019
Journal European Journal of Medicinal Chemistry
Print ISSN 0223-5234
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 162
Pages 631-649
APA6 Citation Adlere, I., Sun, S., Zarca, A., Roumen, L., Gozelle, M., Viciano, C. P., …Leurs, R. (2019). Structure-based exploration and pharmacological evaluation of N-substituted piperidin-4-yl-methanamine CXCR4 chemokine receptor antagonists. European Journal of Medicinal Chemistry, 162, 631-649. doi:10.1016/j.ejmech.2018.10.060
DOI https://doi.org/10.1016/j.ejmech.2018.10.060
Keywords Organic Chemistry; Pharmacology; Drug Discovery; General Medicine
Publisher URL https://www.sciencedirect.com/science/article/pii/S0223523418309371?via%3Dihub

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