Conformation-function relationships for tetragastrin analogues

G. V. Nikiforovich, I. T. Liepina, V. M. Tseytin, M. D. Shenderovich, S. G. Galaktionov

Institute of Organic Synthesis, Latvian Academy of Sciences, Riga; All-Union Research Institute of Microbiological Industry, Minsk

Abstract: Sets of low-energy backbone conformations of the active tetragastrin analogue Boc-Trp-Leu-Asp-Phe-NH₂ and two competitive antagonists Boc-Trp-Leuψ(CH₂NH)-Asp-Phe-NH₂ and Boc-Trp-Leu-Asp-O-CH₂-CH₂-C6H₅ were obtained using theoretical con-formational analysis methods. Groups of the conformations were selected for the three analogues, allowing a spatial matching of Trp, Asp and Phe residues responsible for the gastrin receptor binding. Three conformations possessing the lowest energies among the geometrically similar structures of these three peptides are suggested as a model for the «receptor-bound» conformations of these analogues. Backbone spatial folding resembling an α-helix turn is characteristic of these conformations. The correspondence of the proposed model to the available data on structure–activity relationships for tetragastrin analogues is discussed. Orientations of the putative receptor-bound conformations in a “water – lypophylic medium” two-phase system were investigated.

Russian Journal of Bioorganic Chemistry 1991, 17 (5):626-636

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