CoMFA investigations on two series of artificial peptide inhibitors of the serine protease thermitase. Synthesis of an inhibitor of predicted greater potency.
Comparative molecular field analysis (CoMFA) is shown to be a very useful tool in treating two series of artificial substrate analogue inhibitors, peptide methyl ketones and chloromethyl ketones, of the serine protease thermitase. The backbone structure of the native polypeptide eglin c found in the X-ray structure of its complex with the enzyme served as a template for the alignment of the inhibitors, which could be shown to be the key for success. Restricted only by the relatively small number of different amino acids representing the peptide sequence we were able to determine the regions of the compounds that are important for the value of the inhibitor constant K(i). On the basis of these results we have suggested some new structures with possibly increased inhibitory activity. One such structure was synthesized and is shown to be the most active compound tested up to now, with an experimental K(i)-value in the predicted range.
Brandt
W
W
Department of Biochemistry/Biotechnology, Martin-Luther University of Halle-Wittenberg, Germany.
Lehmann
T
T
Willkomm
C
C
Fittkau
S
S
Barth
A
A
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D015195:Drug Design; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008848:Micromonosporaceae / Q000201:enzymology*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011506:Proteins; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015843:Serpins / Q000737:chemistry / Q000494:pharmacology
D007659:Ketones; D009842:Oligopeptides; D011506:Proteins; D015842:Serine Proteinase Inhibitors; D015843:Serpins; C028656:eglin proteinase inhibitors; D012697:Serine Endopeptidases; C022728:thermitase