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

Adlere, Ilze; Sun, Shan-Liang; Zarca, Aurélien; Roumen, Luc; Gozelle, Mahmut; Perpiñá-Viciano, Cristina; Caspar, Birgit; Arimont, Marta; Bebelman, Jan Paul; Briddon, Stephen J.; Hoffmann, Carsten; Hill, Stephen J.; Smit, Martine J.; Vischer, Henry F.; Graaf, Chris de; Esch, Iwan J. P. de; Leurs, Rob

doi:10.1016/j.ejmech.2018.10.060

Cited by 13 publications

(13 citation statements)

References 74 publications

(118 reference statements)

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“…4). Adlere et al (2019) showed that small structural ligand changes lead to distinct interactions with CXCR4 and CXCL12, supporting the study with three-dimensional quantitative SAR (3D-QSAR) and proposed binding models.…”

Section: Downloaded Fromsupporting

confidence: 76%

Modulators of CXCR4 and CXCR7/ACKR3 Function

et al. 2019

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The two G protein-coupled receptors (GPCRs) C-X-C chemokine receptor type 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) are part of the class A chemokine GPCR family and represent important drug targets for human immunodeficiency virus (HIV) infection, cancer, and inflammation diseases. CXCR4 is one of only three chemokine receptors with a US Food and Drug Administration approved therapeutic agent, the smallmolecule modulator AMD3100. In this review, known modulators of the two receptors are discussed in detail. Initially, the structural relationship between receptors and ligands is reviewed on the basis of common structural motifs and available crystal structures. To date, no atypical chemokine receptor has been crystallized, which makes ligand design and predictions for these receptors more difficult. Next, the selectivity, receptor activation, and the resulting ligand-induced signaling output of chemokines and other peptide ligands are reviewed. Binding of pepducins, a class of lipid-peptides whose basis is the internal loop of a GPCR, to CXCR4 is also discussed. Finally, small-molecule modulators of CXCR4 and ACKR3 are reviewed. These modulators have led to the development of radio-and fluorescently labeled tool compounds, enabling the visualization of ligand binding and receptor characterization both in vitro and in vivo. SIGNIFICANCE STATEMENTTo investigate the pharmacological modulation of CXCR4 and ACKR3, significant effort has been focused on the discovery and development of a range of ligands, including small-molecule modulators, pepducins, and synthetic peptides. Imaging tools, such as fluorescent probes, also play a pivotal role in the field of drug discovery. This review aims to provide an overview of the aforementioned modulators that facilitate the study of CXCR4 and ACKR3 receptors.

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Section: Downloaded Fromsupporting

confidence: 76%

Modulators of CXCR4 and CXCR7/ACKR3 Function

et al. 2019

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“…1, 2, and 3A). The (partial) overlap explains the different levels of chemokine displacement that are observed in experiments using different small molecule (potentially allosteric) modulators (Adlere et al, 2019). Moreover, the orthosteric binding site is divided into a minor subpocket and a major subpocket (Fig.…”

Section: Chemokine Receptor Structuresmentioning

confidence: 99%

“…Analysis of key interactions in crystal structures offers a rationale for designing ligand modifications. To illustrate, a recent study focused on the IT1t-bound CXCR4 crystal structure as a baseline to identify new fragment hits and analyzed the crystal structure to rationally design a fragment growing strategy (Adlere et al, 2019). In this study, the identification of a highly hydrophobic hotspot in the binding site of the cocrystallized ligand was Lessons from Chemokine Receptor X-Ray Structures used to generate analogs with increased lipophilicity to target the hotspot.…”

Section: Applications Of Chemokine Receptor Crystal Structures For Momentioning

confidence: 99%

Chemokine Receptor Crystal Structures: What Can Be Learned from Them?

et al. 2019

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Chemokine receptors belong to the class A of G protein-coupled receptors (GPCRs) and are implicated in a wide variety of physiologic functions, mostly related to the homeostasis of the immune system. Chemokine receptors are also involved in multiple pathologic processes, including immune and autoimmune diseases, as well as cancer. Hence, several members of this GPCR subfamily are considered to be very relevant therapeutic targets. Since drug discovery efforts can be significantly reinforced by the availability of crystal structures, substantial efforts in the area of chemokine receptor structural biology could dramatically increase the outcome of drug discovery campaigns. This short review summarizes the available data on chemokine receptor crystal structures, discusses the numerous applications from chemokine receptor structures that can enhance the daily work of molecular pharmacologists, and describes the challenges and pitfalls to consider when relying on crystal structures for further research applications. SIGNIFICANCE STATEMENT This short review summarizes the available data on chemokine receptor crystal structures, discusses the numerous applications from chemokine receptor structures that can enhance the daily work of molecular pharmacologists, and describes the challenges and pitfalls to consider when relying on crystal structures for further research applications.

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“…The resulting nucleotide fragment (sig.LgBiT) contained the sequences for the restriction enzyme KpnI upstream of the sig sequence and the restriction enzyme BamHI downstream of the linker. This was then ligated to the pcDNA3.1(+) plasmid containing the human CXCR4 receptor (described in Adlere et al, 2019 ), creating the fusion of sig.LgBiT, a Gly-Ser linker and CXCR4 with the methionine start signal removed.…”

Section: Methodsmentioning

confidence: 99%