Studies on the interactions between lactam analogs and the N-terminal extracellular tail of CC chemokine receptor 4 by CZE.
CC chemokine receptor 4 (CCR4) is a kind of G-protein-coupled receptors with a characteristic seven-transmembrane structure and selectively expressed on Th2-type CD4+ T-cells, which play a pivotal role in allergic inflammation. In this study, the interactions between 2-(2-(2,4-dichloro-phenyl)-4-{[(2-methyl-3-chloro-phenyl)-1-ylmethyl]-carbamoyl}-methyl)-5-oxo-pyrrole-1-yl)-N-(3-piperidinyl-propyl)-acetamide (compound A), a known CCR4 antagonist, and ML40 were studied by CZE for the first time. Both qualitative and quantitative characterizations of the drug-peptide binding were determined. The binding constant of the interaction between the trans-diastereomer of compound A and ML40, calculated from the Scatchard plot by regression, was (1.06 +/- 0.11)x10(5)/M. Also, it was confirmed that the trans-diastereomer was more potent affinity with CCR4 than its cis-counterpart. The experimental results show that this reported method by CZE for the determination of the compound A and ML40 interactions is powerful, sensitive, and fast, requires less amounts of reagents, and further, it can be employed as one of the reliable screening methods to a series of lactam analogs in the drug discovery for allergic inflammation diseases.
Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences, Peking University, Beijing, PR China.
Zhe
Z
Sun
Xiaomei
X
Ling
Wei
W
Sun
Junhai
J
Xiao
Caihua
C
Yin
Ying
Y
Wang
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019075:Electrophoresis, Capillary / Q000379:methods*; D008969:Molecular Sequence Data; D010880:Piperidines / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry*; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013237:Stereoisomerism
C525000:(((2-(2-(2,4-dichlorophenyl)-4-(2-methyl-3-chlorophenyl)-1-ylmethyl)carbamoyl)methyl)-5-oxopyrrole-1-yl)-N-(3-piperidinylpropyl)acetamide; D010880:Piperidines; D011758:Pyrroles; D054398:Receptors, CCR4