Insight into structural requirements for selective and/or dual CXCR3 and CXCR4 allosteric modulators

Kolarič, Anja; Švajger, Urban; Tomašič, Tihomir; Brox, Regine; Frank, Theresa; Minovski, Nikola; Tschammer, Nuška; Anderluh, Marko

doi:10.1016/j.ejmech.2018.05.013

Cited by 3 publications

(4 citation statements)

References 62 publications

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“…Given the importance of CXCR4 in different diseases, the structure–function relationship of CXCR4 has been studied using computational techniques to understand its functional dynamics after ligand binding − and the effects of the mutations on its activation. , Its tendency to oligomerize with itself and other proteins, which offers additional targets for the design of novel inhibitors, has been also studied using computational and experimental techniques. − Allosteric behaviors of CXCR4 have been investigated and several modulators have been developed. ,,− Modulator binding sites are often located on the extracellular or transmembrane regions of the protein. However, CXCR4 may also accommodate intramembrane binding sites as observed with the free fatty acid receptor GPR40, − purinergic P2Y1 receptor, protease-activated receptor 2 PAR2, and human melatonin receptors MT1 and MT2, , which are all GPCRs with intramembrane binding sites.…”

Section: Introductionmentioning

confidence: 99%

“… 27 , 32 Its tendency to oligomerize with itself and other proteins, which offers additional targets for the design of novel inhibitors, has been also studied using computational and experimental techniques. 33 − 35 Allosteric behaviors of CXCR4 have been investigated 36 and several modulators have been developed. 20 , 21 , 36 − 39 Modulator binding sites are often located on the extracellular or transmembrane regions of the protein.…”

Section: Introductionmentioning

confidence: 99%

“… 33 − 35 Allosteric behaviors of CXCR4 have been investigated 36 and several modulators have been developed. 20 , 21 , 36 − 39 Modulator binding sites are often located on the extracellular or transmembrane regions of the protein. However, CXCR4 may also accommodate intramembrane binding sites as observed with the free fatty acid receptor GPR40, 40 − 42 purinergic P2Y1 receptor, 43 protease-activated receptor 2 PAR2, 44 and human melatonin receptors MT1 and MT2, 45 , 46 which are all GPCRs with intramembrane binding sites.…”

Section: Introductionmentioning

confidence: 99%

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Identifying and Assessing Putative Allosteric Sites and Modulators for CXCR4 Predicted through Network Modeling and Site Identification by Ligand Competitive Saturation

Inan,

Flinko,

Lewis

et al. 2024

J. Phys. Chem. B

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The chemokine receptor CXCR4 is a critical target for the treatment of several cancer types and HIV-1 infections. While orthosteric and allosteric modulators have been developed targeting its extracellular or transmembrane regions, the intramembrane region of CXCR4 may also include allosteric binding sites suitable for the development of allosteric drugs. To investigate this, we apply the Gaussian Network Model (GNM) to the monomeric and dimeric forms of CXCR4 to identify residues essential for its local and global motions located in the hinge regions of the protein. Residue interaction network (RIN) analysis suggests hub residues that participate in allosteric communication throughout the receptor. Mutual residues from the network models reside in regions with a high capacity to alter receptor dynamics upon ligand binding. We then investigate the druggability of these potential allosteric regions using the site identification by ligand competitive saturation (SILCS) approach, revealing two putative allosteric sites on the monomer and three on the homodimer. Two screening campaigns with Glide and SILCS-Monte Carlo docking using FDA-approved drugs suggest 20 putative hit compounds including antifungal drugs, anticancer agents, HIV protease inhibitors, and antimalarial drugs. In vitro assays considering mAB 12G5 and CXCL12 demonstrate both positive and negative allosteric activities of these compounds, supporting our computational approach. However, in vivo functional assays based on the recruitment of β-arrestin to CXCR4 do not show significant agonism and antagonism at a single compound concentration. The present computational pipeline brings a new perspective to computer-aided drug design by combining conformational dynamics based on network analysis and cosolvent analysis based on the SILCS technology to identify putative allosteric binding sites using CXCR4 as a showcase.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identifying and Assessing Putative Allosteric Sites and Modulators for CXCR4 Predicted through Network Modeling and Site Identification by Ligand Competitive Saturation

Inan,

Flinko,

Lewis

et al. 2024

J. Phys. Chem. B

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“…Its cognate ligand is the chemokine CXCL12 (also named stromal cell-derived factor-1α, SDF-1α) [2,3]. Given its prominent roles in tumor metastasis and inflammation, CXCR4 has gained plenty of attention in the recent decade [4][5][6][7]. Evidence has proven that the CXCR4/CXCL12 axis can chemotactically recruit inflammatory cells (neutrophils, monocytes, and lymphocytes) to local tissues and regulate the release of inflammatory factors that cause inflammatory responses [8,9].…”

Section: Introductionmentioning

confidence: 99%

Development of CXCR4 modulators based on the lead compound RB-108

Bai

Jie

Sun

et al. 2019

European Journal of Medicinal Chemistry

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The CXCR4/CXCL12 axis plays prominent roles in tumor metastasis and inflammation. CXCR4 has been shown to be involved in a variety of inflammation-related diseases. Therefore, CXCR4 is a promising potential target to develop novel anti-inflammatory agents. Taking our previously discovered CXCR4 modulator RB-108 as the lead compound, a series of derivatives were synthesized structurally modifying and optimizing the amide and sulfamide side chains. The derivatives successfully maintained potent CXCR4 binding affinity. Furthermore, compounds Ilb, IIc, IIIg, IIIj, and IIIm were all efficacious in inhibiting the invasion of CXCR4-positive cells, displaying a much more potent effect than the lead compound RB-108. Notably, compound IIIm significantly decreased carrageenan-induced swollen volume and paw thickness in a mouse paw edema model. More importantly, IIIm exhibited satisfying PK profiles with a half-life of 4.77 h in an SD rat model. In summary, we have developed compound IIIm as a new candidate for further investigation based on the lead compound RB-108.

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Discovery of novel CXCR4 inhibitors for the treatment of inflammation by virtual screening and biological evaluation

Wang,

Ma,

Yang

et al. 2024

European Journal of Medicinal Chemistry

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Insight into structural requirements for selective and/or dual CXCR3 and CXCR4 allosteric modulators

Cited by 3 publications

References 62 publications

Identifying and Assessing Putative Allosteric Sites and Modulators for CXCR4 Predicted through Network Modeling and Site Identification by Ligand Competitive Saturation

Identifying and Assessing Putative Allosteric Sites and Modulators for CXCR4 Predicted through Network Modeling and Site Identification by Ligand Competitive Saturation

Development of CXCR4 modulators based on the lead compound RB-108

Discovery of novel CXCR4 inhibitors for the treatment of inflammation by virtual screening and biological evaluation

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