title: Identification of Two Distinct Sites for Antagonist and Biased Agonist Binding to the Human Chemokine Receptor CXCR3.
abstract: The chemokine receptor CXCR3 is a G protein-coupled receptor that conveys extracellular signals into cells by changing its conformation upon ligand binding. We previously hypothesized that small-molecule allosteric CXCR3-agonists do not bind to the same allosteric binding pocket as 8-azaquinazolinone-based negative allosteric modulators. We have now performed molecular-dynamics (MD) simulations with metadynamics enhanced sampling on the CXCR3 system to refine structures and binding modes and to predict the CXCR3-binding affinities of the biased allosteric agonist FAUC1036 and the negative allosteric modulator RAMX3. We have identified two distinct binding sites; a "shallow" and a second "deeper" pocket to which the biased allosteric agonist FAUC1036 and negative allosteric modulator RAMX3 bind, respectively.
authors.affiliation: Computer-Chemie-Centrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nägelsbachstr. 25, 91052, Erlangen, Germany.|Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, 91052, Erlangen, Germany.
authors.forename: Lampros
authors.initials: L
authors.lastname: Milanos
authors.affiliation: Computer-Chemie-Centrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nägelsbachstr. 25, 91052, Erlangen, Germany.
authors.forename: Noureldin
authors.identifier: 0000-0002-5116-2312
authors.initials: N
authors.lastname: Saleh
authors.affiliation: Computer-Chemie-Centrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nägelsbachstr. 25, 91052, Erlangen, Germany.|Institute of Physiology, Paracelsus Medical University Nürnberg, Prof.-Ernst-Nathan-Str. 1, 90419, Nürnberg, Germany.
authors.forename: Ralf C
authors.identifier: 0000-0002-3829-4353
authors.initials: RC
authors.lastname: Kling
authors.affiliation: Computer-Chemie-Centrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nägelsbachstr. 25, 91052, Erlangen, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Kaindl
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, 91052, Erlangen, Germany.|Research and Development, NanoTemper Technologies GmbH, Floessergasse 4, 81369, München, Germany.
authors.forename: Nuska
authors.identifier: 0000-0003-2433-3355
authors.initials: N
authors.lastname: Tschammer
authors.affiliation: Computer-Chemie-Centrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nägelsbachstr. 25, 91052, Erlangen, Germany.
authors.forename: Timothy
authors.identifier: 0000-0001-7931-4659
authors.initials: T
authors.lastname: Clark
mesh_terms: D000081:Acetamides / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D006801:Humans; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology*; D054367:Receptors, CXCR3 / Q000819:agonists* / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000081:Acetamides; C515187:CXCR3 protein, human; D011744:Pyrimidinones; C576504:RAMX3; D054367:Receptors, CXCR3; D054852:Small Molecule Libraries
keywords: allosterism; membrane proteins; molecular dynamics; protein structures; signal transduction