title: Molecular Pharmacology of Chemokine Receptors.
abstract: Chemokine receptors are involved in various pathologies such as inflammatory diseases, cancer, and HIV infection. Small molecule and antibody-based antagonists have been developed to inhibit chemokine-induced receptor activity. Currently two small molecule inhibitors targeting CXCR4 and CCR5 are on the market for stem cell mobilization and the treatment of HIV infection, respectively. Antibody fragments (e.g., nanobodies) targeting chemokine receptors are primarily orthosteric ligands, competing for the chemokine binding site. This is opposed by most small molecules, which act as allosteric modulators and bind to the receptor at a topographically distinct site as compared to chemokines. Allosteric modulators can be distinguished from orthosteric ligands by unique features, such as a saturable effect and probe dependency. For successful drug development, it is essential to determine pharmacological parameters (i.e., affinity, potency, and efficacy) and the mode of action of potential drugs during early stages of research in order to predict the biological effect of chemokine receptor targeting drugs in the clinic. This chapter explains how the pharmacological profile of chemokine receptor targeting ligands can be determined and quantified using binding and functional experiments.
authors.affiliation: Amsterdam Institute for Molecules Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.
authors.forename: Raymond H
authors.initials: RH
authors.lastname: de Wit
authors.affiliation: Amsterdam Institute for Molecules Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.
authors.forename: Sabrina M
authors.initials: SM
authors.lastname: de Munnik
authors.affiliation: Amsterdam Institute for Molecules Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.affiliation: Amsterdam Institute for Molecules Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.
authors.forename: Henry F
authors.initials: HF
authors.lastname: Vischer
authors.affiliation: Amsterdam Institute for Molecules Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Vrije Universiteit, Amsterdam, The Netherlands. Electronic address: mj.smit@vu.nl.
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Smit
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism*; D002633:Chemotaxis; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes; D008024:Ligands; D008967:Molecular Biology / Q000379:methods*; D058990:Molecular Targeted Therapy / Q000379:methods*; D011485:Protein Binding; D019707:Receptors, Chemokine / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071557:beta-Arrestins / Q000378:metabolism
chemical_list: D018925:Chemokines; D007457:Iodine Radioisotopes; D008024:Ligands; D019707:Receptors, Chemokine; D000071557:beta-Arrestins; D016244:Guanosine 5'-O-(3-Thiotriphosphate)
keywords: Allosteric modulation; Binding; Chemokine; Chemotaxis; GPCR; Nanobody; Receptor pharmacology; Signaling; Small molecule