Synthesis, binding affinity and structure–activity relationships of novel, selective and dual targeting CCR2 and CCR5 receptor antagonists

Junker, Anna; Kokornaczyk, Artur K.; Zweemer, Annelien J.M.; Frehland, Bastian; Schepmann, Dirk; Yamaguchi, Junichiro; Itami, Kenichiro; Faust, Andreas; Hermann, Sven; Wagner, Stefan; Schäfers, Michael; Koch, Michael; Weiss, Christina; Heitman, Laura H.; Kopka, Klaus; Wünsch, Bernhard

doi:10.1039/c4ob02397h

Cited by 14 publications

(15 citation statements)

References 55 publications

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“…CCR5 would provide an accurate template to construct a 19 bound CCR2 homology model. 22 As pointed out before by others, 23 the 31 bound CXCR4 crystal structure (PDB 3ODU) contains two protruding lipids in the major pocket between TM5 and TM6, which constitute a crystallization artifact that conditions the orientation of these two helices. For ligand-bound models in which important interactions are characterized in the major pocket, the CVX15-bound structure may constitute a better template.…”

Section: Experimentally Informed Modeling Of Chemokine Receptor–liganmentioning

confidence: 83%

“…17−19 The first crystal structures of the 7TM domains of chemokine receptors (CXCR4, CCR2, CCR5, CCR9, and US28) have been solved only in the past six years. 11−16 These small-molecule, 12,15,16 peptide, 11 and chemokine 13,14 bound structures have provided a structural basis to validate and improve chemokine receptor homology modeling studies, 20 to rationalize SAR data 21,22 and to perform structure-based virtual screening and ligand design studies. 23−30 Chemokine homology models and de novo receptor models have already been successfully used to identify new ligands for CCR3, 31 CCR4, 32,33 CCR5, 34,35 CXCR3, 26 CXCR4, 24,26−30,36,37 and CXCR7, 38 and the recently released crystal structures have increased the possibilities to study and predict structural chemokine receptor–ligand interactions.…”

Section: Introductionmentioning

confidence: 99%

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Structural Analysis of Chemokine Receptor–Ligand Interactions

et al. 2017

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This review focuses on the construction and application of structural chemokine receptor models for the elucidation of molecular determinants of chemokine receptor modulation and the structure-based discovery and design of chemokine receptor ligands. A comparative analysis of ligand binding pockets in chemokine receptors is presented, including a detailed description of the CXCR4, CCR2, CCR5, CCR9, and US28 X-ray structures, and their implication for modeling molecular interactions of chemokine receptors with small-molecule ligands, peptide ligands, and large antibodies and chemokines. These studies demonstrate how the integration of new structural information on chemokine receptors with extensive structure–activity relationship and site-directed mutagenesis data facilitates the prediction of the structure of chemokine receptor–ligand complexes that have not been crystallized. Finally, a review of structure-based ligand discovery and design studies based on chemokine receptor crystal structures and homology models illustrates the possibilities and challenges to find novel ligands for chemokine receptors.

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Section: Experimentally Informed Modeling Of Chemokine Receptor–liganmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Structural Analysis of Chemokine Receptor–Ligand Interactions

et al. 2017

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“…A group of 41 known CCR5 inhibitors, characterized by their excellent experimental performances (IC 50 ≤ 10 nM), including Maraviroc, Ancriviroc, Aplaviroc, INCB-9471 and SCH-350634 ( Figure 2), were collected from previous literatures [32][33][34][35][36][37][38]. A decoy set based on the chemical structure of Maraviroc was generated from the online server Database of Useful Decoys: Enhanced (DUD.E) [39], which provides a set of 393 decoys that are available from the online ZINC database.…”

Section: Receptor Ligands Database Preparationmentioning

confidence: 99%

Structure-Based Pharmacophore Modeling to Discover Novel CCR5 Inhibitors for HIV-1/Cancers Therapy

Lin

Ho²,

Liu

2019

JBiSE

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CC chemokine receptor 5 (CCR5), a member of G protein-coupled receptors (GPCRs), not only plays a significant role in inflammatory responses, but also correlates with HIV-1 infection and cancer progression. Recently, blocking of CCR5 has been considered as an effective strategy in HIV-1/cancers therapy. So far, only Maraviroc has been approved by FDA in 2007, while the other CCR5 inhibitors have failed in their clinical trials. In this study, a highly selective structure-based pharmacophore model was constructed, validated, and applied for virtual screening to retrieve novel CCR5 inhibitors from NCI database. Finally, one potential CCR5 inhibitor candidate, NSC13165, was identified after molecular docking, molecular dynamics (MD) simulations, binding free energy analyses and ADMET prediction. Docking and MD simulation results not only suggested that NSC13165 reserves the common binding mode of the most known CCR5 inhibitors, but also provided important insights toward the allosteric inhibition mechanism of CCR5. The results of binding free energy analyses indicated that the binding affinity of NSC13165 is much better than that of Maraviroc and that van der Waals interaction is the key driving force during the binding process. ADMET prediction suggested that NSC13165 exhibits very low risk of causing lethal side effects. Altogether, our results strongly suggest that NSC13165 has great potential to serve as a novel CCR5 inhibitor, which may be further tested in vitro/in vivo as a drug target for HIV-1/cancers therapy or be used as a lead compound for improving its efficacy through chemical modifications.

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“…Depending on the substitution pattern, potent CCR2 selective and dual CCR2 and CCR5 targeting antagonists were found. [9][10][11] (1) and .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of chemokine receptor ligands with 2-benzazepine scaffold

Thum

Kokornaczyk

Seki

et al. 2017

European Journal of Medicinal Chemistry

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Targeting CCR2 and CCR5 receptors is considered as promising concept for the development of novel antiinflammatory drugs. Herein, we present the development of the first probe-dependent positive allosteric modulator (PAM) of CCR5 receptors with a 2-benzazepine scaffold. Compound 14 (2-isobutyl-N-({[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl}phenyl)-1-oxo-2,3-dihydro-1H-2-benzazepine-4-carboxamide) activates the CCR5 receptor in a CCL4-dependent manner, but does not compete with [H]TAK-779 binding at the CCR5. Furthermore, introduction of a p-tolyl moiety at 7-position of the 2-benzazepine scaffold turns the CCR5 PAM 14 into the selective CCR2 receptor antagonist 26b. The structure affinity and activity relationships presented here offer new insights into ligand recognition by CCR2 and CCR5 receptors.

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Synthesis, binding affinity and structure–activity relationships of novel, selective and dual targeting CCR2 and CCR5 receptor antagonists

Cited by 14 publications

References 55 publications

Structural Analysis of Chemokine Receptor–Ligand Interactions

Structural Analysis of Chemokine Receptor–Ligand Interactions

Structure-Based Pharmacophore Modeling to Discover Novel CCR5 Inhibitors for HIV-1/Cancers Therapy

Synthesis and biological evaluation of chemokine receptor ligands with 2-benzazepine scaffold

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