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.; 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.

doi:10.1016/j.ejmech.2018.10.060

Authors

I. Adlere

S. Sun

A. Zarca

L. Roumen

M. Gozelle

Viciano

B. Caspar

M. Arimont

J.P. Bebelman

STEPHEN BRIDDON stephen.briddon@nottingham.ac.uk
Principal Research Fellow

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.

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. https://doi.org/10.1016/j.ejmech.2018.10.060

Journal Article Type	Article
Acceptance Date	Oct 27, 2018
Online Publication Date	Oct 30, 2018
Publication Date	Jan 15, 2019
Deposit Date	Dec 21, 2018
Publicly Available Date	Oct 31, 2019
Journal	European Journal of Medicinal Chemistry
Print ISSN	0223-5234
Electronic ISSN	1768-3254
Publisher	Elsevier
Peer Reviewed	Peer Reviewed
Volume	162
Pages	631-649
DOI	https://doi.org/10.1016/j.ejmech.2018.10.060
Keywords	Organic Chemistry; Pharmacology; Drug Discovery; General Medicine
Public URL	https://nottingham-repository.worktribe.com/output/1433796
Publisher URL	https://www.sciencedirect.com/science/article/pii/S0223523418309371?via%3Dihub