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. Perpi��; 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.

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., Caspar, B., Arimont, M., Bebelman, J., Briddon, S., Hoffmann, C., Hill, S., Smit, M., Vischer, H., Wijtmans, M., de Graaf, C., de Esch, I., & 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
• Contract Date: Dec 21, 2018