title: Functional assays as prismatic views of drug activity: relevance to new drug discovery.
abstract: The two main processes involved in new drug discovery are screening and lead optimization; the latter process encompasses the dialogue between pharmacologists and medicinal chemists with the aim of maximizing primary activity and druglike properties of compounds. The pharmacological assay is the main tool in both of these processes; this will be discussed with special attention to new information regarding the signaling and networking of seven transmembrane receptors. In particular, the assays used for lead optimization will be discussed in terms of detecting and developing drugs that specifically emphasize some signaling pathways and not others, all through the stabilization of unique receptor protein conformations. There is considerable data to indicate that these are real phenomena that may be exploited for therapeutic advantage. A therapeutically relevant example will be discussed from a recent program designed to block entry of HIV-1 for the prevention and therapy of AIDS. The allosteric modulator aplaviroc (873140) and other allosteric modulators will be highlighted with reference to the development of future drugs that block the involvement of receptors in pathological process but otherwise allow them to function normally. In AIDS, this would allow the natural chemokine systems to assist in the protection against further HIV-1 infection.
authors.affiliation: GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, USA. Terry.P.Kenakin@gsk.com
authors.forename: Terry
authors.initials: T
authors.lastname: Kenakin
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000517:prevention & control; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008954:Models, Biological; D010600:Pharmacology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D043562:Receptors, G-Protein-Coupled