Chapter 12. The use of receptor homology modeling to facilitate the design of selective chemokine receptor antagonists.

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.