Identifying modulators of CXC receptors 3 and 4 with tailored selectivity using multi-target docking
Schmidt D, Bernat V, Brox R, Tschammer N, Kolb P (2015)
Publication Type: Journal article
Publication year: 2015
Journal
Book Volume: 10
Pages Range: 715-724
Journal Issue: 3
DOI: 10.1021/cb500577j
Abstract
The G protein-coupled receptors of the C-X-C subfamily form a group among the chemokine receptors whose endogenous ligands are peptides with a common Cys-X-Cys motif. The CXC chemokine receptors 3 and 4 (CXCR3, CXCR4), which are investigated in this study, are linked to severe diseases such as cancer, multiple sclerosis, and HIV infections. Of particular interest, this receptor pair potentially forms a target for a polypharmacological drug treatment. Considering known ligands from public databases, such dual binders have not been identified yet. We therefore applied large-scale docking to the structure of CXCR4 and a homology model of CXCR3 with the goal to predict such dual binders, as well as compounds selective for either one of the receptors. Using signaling and biochemical assays, we showed that more than 50% of these predictions were correct in each category, yielding ligands with excellent binding efficiencies. These results highlight that docking is a suitable tool for the identification of ligands with tailored binding profiles to GPCRs, even when using homology models. More importantly, we present novel CXCR3-CXCR4 dual modulators that might pave the road to understanding the mechanisms of polypharmacological inhibition of these receptors.
Authors with CRIS profile
Viachaslau Bernat
Lehrstuhl für Pharmazeutische Chemie
Regine Brox
Department of Transfusion Medicine and Haemostaseology
Nuska Tschammer
Lehrstuhl für Pharmazeutische Chemie
Involved external institutions
Germany (DE)How to cite
APA:
Schmidt, D., Bernat, V., Brox, R., Tschammer, N., & Kolb, P. (2015). Identifying modulators of CXC receptors 3 and 4 with tailored selectivity using multi-target docking. ACS Chemical Biology, 10(3), 715-724. https://dx.doi.org/10.1021/cb500577j
MLA:
Schmidt, Denis, et al. "Identifying modulators of CXC receptors 3 and 4 with tailored selectivity using multi-target docking." ACS Chemical Biology 10.3 (2015): 715-724.
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