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