title: Exploring the binding pocket for pyridopyrimidine ligands at the CCK1 receptor by molecular docking.
abstract: Pyridopyrimidine-based analogues are among the most highly potent and selective antagonists of cholecystokinin receptor subtype-1 (CCK1R) described to date. To better understand the structural and chemical features responsible for the recognition mechanism, and to explore the binding pocket of these compounds, we performed automated molecular docking using GOLD2.2 software on some derivatives with structural diversity, and propose a putative binding conformation for each compound. The docking protocol was guided by the key role of the Asn333 residue, as revealed by site directed mutagenesis studies. The results suggest two putative binding modes located in the same pocket. Both are characterized by interaction with the main residues revealed by experiment, Asn333 and Arg336, and differ in the spatial position of the Boc-Trp moiety of these compounds. Hydrophobic contacts with residues Thr117, Phe107, Ile352 and Ile329 are also in agreement with experimental data. Despite the poor correlation obtained between the estimated binding energies and the experimental activity, the proposed models allow us to suggest a plausible explanation of the observed binding data in accordance with chemical characteristics of the compounds, and also to explain the observed diastereoselectivity of this family of antagonists towards CCK1R. The most reasonable selected binding conformations could be the starting point for future studies. Figure Superimposition of the two putative binding conformations revealed by molecular docking for pyridopyrimidine-based CCK1 antagonists.
authors.affiliation: Laboratoire de Physico-Chimie Théorique et Chimie Informatique, Faculté de CHIMIE, USTHB B.P. 32, El Alia, Alger, Algeria, ameltoumi_usthb@yahoo.fr
authors.forename: Amel
authors.initials: A
authors.lastname: Toumi-Maouche
authors.forename: Boubekeur
authors.initials: B
authors.lastname: Maouche
authors.forename: Safia
authors.initials: S
authors.lastname: Taïri-Kellou
authors.forename: Salima
authors.initials: S
authors.lastname: El-Aoufi
authors.forename: Mercedes
authors.initials: M
authors.lastname: Martín-Martínez
authors.forename: Rosario
authors.initials: R
authors.lastname: González-Muñiz
authors.forename: Daniel
authors.initials: D
authors.lastname: Fourmy
authors.forename: Bernard
authors.initials: B
authors.lastname: Maigret
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D019277:Entropy; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011487:Protein Conformation; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D043886:Receptor, Cholecystokinin A / Q000819:agonists / Q000737:chemistry*; D012984:Software; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011743:Pyrimidines; D043886:Receptor, Cholecystokinin A