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Chemokine receptor antagonists have potential applications in fields as diverse as oncology, immunology, cardiovascular diseases, and virology. Although the chemokine receptors are G-protein-coupled receptors, their cognate ligands are small proteins (8 to 12 kDa), and so inhibiting the ligand/receptor interaction has been challenging. In this chapter, we review the use of receptor mutagenesis to probe the allosteric nature of chemokine receptor binding by small molecule antagonists. We then demonstrate how two different homology modeling templates--a balloon-expanded form of rhodopsin and a modified form of beta(2)-adrenergic receptor--can be used to rationalize the mutagenesis data. With these templates, new models are presented for several antagonist/receptor interactions previously studied in the literature, including those for CCR1, CCR2, and CCR5. We discuss the strengths of both approaches and offer ideas for how the templates themselves can be used in the absence of mutagenesis data to rationalize structure-activity relationships.

Publisher Summary CC Chemokine Receptor 2 (CCR2) is a member of the G protein-coupled receptor (GPCR) superfamily that serves as the receptor for monocyte chemoattractant proteins 1–4 (MCP-1 to -4), a group of pro-inflammatory chemotactic cytokines (chemokines). CCR2 is the primary chemokine receptor on inflammatory monocytes, and is also expressed on T-cells, dendritic cells, and endothelial cells. A number of studies have demonstrated that antagonism of CCR2 and/or MCP-1 reduces disease scores in pre-clinical models of arthritis. Recently, the first reports of the actions of small molecule antagonists in both collagen-induced arthritis (CIA) and adjuvant arthritis models have appeared, and they confirm the earlier findings: blockade of CCR2 reduced disease score. The effects of genetic deletion of CCR2 in mouse CIA showed that CCR2–/– mice exhibited exacerbated disease. CCR2–/–mice developed chronic polyarthritis after infection with Mycobacterium avium, whereas wild-type (WT) littermates did not. Recent data have highlighted that CCR2 plays a more central role in immunology than had been previously anticipated, in that it governs the emigration of activated monocytes from the bone marrow in addition to directing their migration toward certain points of inflammation. New pre-clinical validation for CCR2 antagonism in rodent disease models has also been obtained, using both genetic and chemical approaches.