Differential binding energy: a detailed evaluation of the influence of hydrogen-bonding and hydrophobic groups on the inhibition of thermolysin by phosphorus-containing inhibitors

Two series of phosphorus-containing peptide analogues, 3 (Cbz-Gly- psi (PO sub(2) super(-)CH sub(2))Leu-Xaa) and 4 (Cbz-Gly- psi (PO sub(2) super(-)NH)Leu- psi (CO sub(2))Xaa), have been synthesized and evaluated as inhibitors of the zinc endopeptidase thermolysin. In comparison with the previously...

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Bibliographic Details
Published in:Journal of the American Chemical Society 1991-01, Vol.113 (1), p.297-307
Main Authors: Morgan, Bradley, Scholtz, John M, Ballinger, Marcus D, Zipkin, Ilan D, Bartlett, Paul A
Format: Article
Language:English
Subjects:
analogs
Chemical reactivity
Chemistry
containing
Exact sciences and technology
hydrogen bonding
hydrophobicity
inhibition
Organic chemistry
peptide synthesis
peptides
phosphorus
Reactivity and mechanisms
role
thermolysin
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Summary:Two series of phosphorus-containing peptide analogues, 3 (Cbz-Gly- psi (PO sub(2) super(-)CH sub(2))Leu-Xaa) and 4 (Cbz-Gly- psi (PO sub(2) super(-)NH)Leu- psi (CO sub(2))Xaa), have been synthesized and evaluated as inhibitors of the zinc endopeptidase thermolysin. In comparison with the previously reported phosphonamidates 1, the phosphinates 3 lose only 0.1 kcal/mol in binding affinity, whereas the depsipeptides 4 are bound 2.7 kcal/mol more weakly; these values are contrasted to the 4.0 kcal/mol reduction in binding affinity observed for the phosphonates 2 (Cbz-Gly- psi (PO sub(2) super(-)O)Leu-Xaa) in comparison to 1 (Cbz-Gly- psi (PO sub(2) super(-)NH)Leu-Xaa). The observed effects are interpreted through consideration of the differences in active-site and solvent interactions.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja00001a043