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J Med Chem. 2005 Jul 28;48(15):4842-50.

Combination of molecular modeling, site-directed mutagenesis, and SAR studies to delineate the binding site of pyridopyrimidine antagonists on the human CCK1 receptor.

Author information

1
Instituto de Química Médica (CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain. iqmm317@iqm.csic.es

Abstract

A rational combination of site-directed mutagenesis studies, structure-activity relationships, and dynamic-based docking of pyridopyrimidine-derived CCK1R antagonists into a refined three-dimensional model of the CCK1R allowed us to identify the receptor residues and the ligand functional groups implicated in the molecular recognition process. Our results provided unambiguous evidence that the binding site of these antagonists is overlapping that of the C-terminal tetrapeptide of CCK. In particular, Asn333 and Arg336 residues of the CCK1R are essential for high-affinity binding of these ligands. Moreover, the 2-aryl group in the pyridopyrimidine derivatives shares the same binding pocket as the C-terminal Phe side chain of CCK. Our [pyridopyrimidine.CCK1R] complex model is consistent with previous suggestions concerning the molecular basis that governs functional activity and provides useful considerations about the high CCK1 versus CCK2 selectivity of our derivatives and could contribute to fine-tune the rational design of new molecules with optimized properties.

PMID:
16033264
DOI:
10.1021/jm0501127
[Indexed for MEDLINE]

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