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

• Published in: European journal of medicinal chemistry Vol. 162; pp. 631 - 649
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.01.2019; Elsevier
• Subjects: 3D-QSAR; Antagonists; Chemistry, Medicinal; CXCR4 chemokine receptor; G protein-coupled receptors; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; Structure-activity relationship; Structure-based fragment virtual screening; BRET; G protein-coupled receptors; LLE; SAR; IP; 3D-QSAR; SDF-1; CXCR4; Antagonists; TMD; SBVS; H-bond; IFP; FBLD; QSAR; Structure-activity relationship; MD; Structure-based fragment virtual screening; GPCR; LE; FRET; CXCR4 chemokine receptor; CRYSTAL-STRUCTURE; DOCKING; DISCOVERY; FRAGMENT-LIKE LIGANDS; IN-VITRO; INHIBITION; HISTAMINE H-4; BINDING; MOLECULAR INTERACTION; HIV ENTRY
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.10.060

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. [Display omitted] •A structure-based virtual screening was used to find fragment-like CXCR4 ligands.•Several inhibitors show binding affinity comparable to hallmark antagonist AMD3100.•Key ligands have distinct competition modes with endogenous chemokine CXCL12.•SAR, 3D-QSAR and predicted binding modes of the hit compounds were analyzed.