RESUMEN

The results of investigations in these laboratories of 2-aryl-4-(piperidin-1-yl)butanamines and 1,3,4-trisubstituted pyrrolidines as human CCR5 antagonists have recently been disclosed. To facilitate further development of these antagonists, we have developed a pharmacophore model based on the structure-activity relationships (SAR) and a human CCR5 receptor docking model using the crystal structure of rhodopsin as a template [Palczewski, K., et al. (2000) Science 289, 739-745]. Guided by the receptor docking model, we have mapped the compounds' site of interaction with CCR5 using site-directed mutagenesis experiments. Our results are consistent with a binding site for the two series that is located within a cavity near the extracellular surface formed by transmembrane helices 2, 3, 6, and 7. This site is overlapping yet distinct from that reported for another antiviral agent which binds to CCR5 [Dragic, T., et al. (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 5639-5644].

Asunto(s)

Butanos/química , Antagonistas de los Receptores CCR5 , Modelos Moleculares , Mutagénesis Sitio-Dirigida , Piperidinas/química , Pirrolidinas/química , Receptores CCR5/química , Alanina/genética , Amidas/química , Secuencia de Aminoácidos , Sustitución de Aminoácidos/genética , Animales , Sitios de Unión/genética , Unión Competitiva/genética , Células CHO , Bovinos , Cricetinae , Humanos , Datos de Secuencia Molecular , Estructura Secundaria de Proteína/genética , Compuestos de Amonio Cuaternario/química , Receptores CCR5/biosíntesis , Receptores CCR5/genética , Rodopsina/química , Homología de Secuencia de Aminoácido , Relación Estructura-Actividad