Determination of the optimal position of adjacent proton-donor centers for the activation or inhibition of peptide bond formation – A computational model study

The study reports a computational analysis of the influence of proton donor group adjacent to the reaction center during ester ammonolysis of an acylated diol as a model reaction for peptide bond formation. This analysis was performed using catalytic maps constructed after a detailed scanning of the available space around the reaction centers in different transition states, a water molecule acting as a typical proton donor. The calculations suggest that an adjacent proton donor center can reduce the activation barrier of the rate determining transition states by up to 7.2 kcal/mol, while no inhibition of the reaction can be achieved by such a group.

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► Construction of catalytic maps by detailed scanning of the available space around the reaction centers in different transition states.
► Computational analysis of the influence of proton donor group adjacent to the reaction center during ester ammonolysis.
► Catalytic maps provide a convenient tool to design drug molecules with functional groups oriented appropriately for activation or inhibition of the reaction.