title: How pharmacological receptor theory can guide new drug discovery CCR5 HIV inhibitors in AIDS as a case study.
abstract: The simple concept of quantifying drug activity through measurement of affinity and efficacy is challenged by the discovery, through new assay technologies, that ligands may have different 'efficacies' for different receptor-driven cellular processes. Thus, a ligand may directly produce the complete behavior pattern of the endogenous natural agonist or only portions of this pattern; the challenge is to quantify these differences in ligands and identify the therapeutically useful phenotypes. Another effect, related to the allosteric nature of the 7-transmembrane domain superfamily of receptors, is the ability of molecules to co-bind to receptors (like antagonists) and selectively modify the effects of endogenous agonists, in essence to filter effects and produce a different pattern of signaling. One realm where this may be useful is the blockade of pathologically related effects of receptors that otherwise are needed for normal physiology. These concepts are illustrated in the context of new allosteric CCR5 HIV-1 entry inhibitors. The allosteric properties of probe dependence and texture in antagonism are related to potential advantages in sparing of normal physiological function and reduction in susceptibility to viral resistance.
authors.affiliation: Department of Biological Reagents and Assay Development, GlaxoSmithKline Research and Development, Research Triangle Park, NC, USA. Terry.P.Kenakin@gsk.com
authors.forename: Terry
authors.initials: T
authors.lastname: Kenakin
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D019713:Receptors, CCR5 / Q000187:drug effects*; D011955:Receptors, Drug / Q000187:drug effects* / Q000235:genetics*
chemical_list: D019380:Anti-HIV Agents; D019713:Receptors, CCR5; D011955:Receptors, Drug