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Exploring the binding pocket for pyridopyrimidine ligands at the CCK1 receptor by molecular docking

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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.

Superimposition of the two putative binding conformations revealed by molecular docking for pyridopyrimidine-based CCK1 antagonists

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Acknowledgments

The authors thank the “Comité Mixte d’Evaluation et de prospection de la cooperation Interuniversitaire Franco-Algérienne” (CMEP) for financial support within the “TASSILI” program. Amel Toumi-Maouche also wishes to warmly thank Vincent Leroux, Alexandre Beautrait, Matthieu Chavent, Jean Paul Becker and Yasmine Asses for their assistance and helpful discussions.

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Authors and Affiliations

  1. Laboratoire de Physico-Chimie Théorique et Chimie Informatique, Faculté de CHIMIE, USTHB B.P. 32, El Alia, Alger, Algeria

    Amel Toumi-Maouche, Boubekeur Maouche, Safia Taïri-Kellou & Salima El-Aoufi

  2. Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006, Madrid, Spain

    Mercedes Martín-Martínez & Rosario González-Muñiz

  3. Equipe de Biologie et Pathologie Digestive, INSERM U531, Institut Louis Bugnard, CHU Rangueil, Bâtiment L3, 31403, Toulouse cedex 4, France

    Daniel Fourmy

  4. Laboratoire Lorrain de Recherche en Informatique et ses Applications, LORIA-615, Rue du Jardin Botanique, 54600, Villers Les-Nancy, France

    Bernard Maigret

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  1. Amel Toumi-Maouche
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  2. Boubekeur Maouche
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  3. Safia Taïri-Kellou
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  4. Salima El-Aoufi
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  5. Mercedes Martín-Martínez
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  6. Rosario González-Muñiz
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  7. Daniel Fourmy
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  8. Bernard Maigret
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Correspondence to Amel Toumi-Maouche.

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Toumi-Maouche, A., Maouche, B., Taïri-Kellou, S. et al. Exploring the binding pocket for pyridopyrimidine ligands at the CCK1 receptor by molecular docking. J Mol Model 14, 303–314 (2008). https://doi.org/10.1007/s00894-008-0271-6

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  • DOI: https://doi.org/10.1007/s00894-008-0271-6

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