Quantitative structure-activity relationship (QSAR) study of elastase substrates and inhibitors.
One hundred Suc-X-Y-Ala-pNA peptides: (Suc: succinyl, pNA: p-nitroanilide, X, Y: Gly, Ala, Val, Leu, Ile, Phe, Pro, alpha-aminobutyric acid, norvaline, norleucine) were synthesized and their reaction constants with porcine pancreatic elastase (Km, kcat and kcat/Km) were determined. These reaction constants were quantitatively analyzed using the Free-Wilson/Fujita-Ban method. The contribution of amino acid side chains to the reaction constants Km, kcat and kcat/Km, expressed logarithmically, was found to be additive. On the other hand, 19 elastase inhibitors of the general formula CF3CO-X-Y-Ala-pNA (X,Y: ten amino acids) were synthesized, and their inhibition constants were compared with the Michaelis constant for the corresponding substrates and analyzed using free-energy-related substituent constants. In the analysis of amino acid side chains in the Y position, the Ki value of the inhibitor was generally correlated to the Km value of the substrate, which corresponded to the inhibitor, thus confirming the validity of the equation. log(1/Ki) = 1.271 log(1/Km) + 4.831 This study may serve as a prototypical approach to unraveling structure-activity relationships of peptide substrates and inhibitors of medicinal or agricultural importance.
Nomizu
M
M
Pharmaceutical Laboratory, Kirin Brewery Co. Ltd., Gunma, Japan.
Iwaki
T
T
Yamashita
T
T
Inagaki
Y
Y
Asano
K
K
Akamatsu
M
M
Fujita
T
T
D000595:Amino Acid Sequence; D007700:Kinetics; D008969:Molecular Sequence Data; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010455:Peptides / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014269:Trifluoroacetic Acid / Q000737:chemistry
D010455:Peptides; D014269:Trifluoroacetic Acid; D010196:Pancreatic Elastase