Quantitative structure-activity relationship (QSAR) study of elastase substrates and inhibitors

• Published in: International journal of peptide and protein research Vol. 42; no. 3; p. 216
• Main Authors: Nomizu, M, Iwaki, T, Yamashita, T, Inagaki, Y, Asano, K, Akamatsu, M, Fujita, T
• Format: Journal Article
• Language: English
• Published: Denmark 01.09.1993
• Subjects: Amino Acid Sequence; Kinetics; Molecular Sequence Data; Pancreatic Elastase - antagonists & inhibitors; Pancreatic Elastase - metabolism; Peptides - chemical synthesis; Peptides - metabolism; Peptides - pharmacology; Structure-Activity Relationship; Substrate Specificity; Trifluoroacetic Acid - chemistry
• ISSN: 0367-8377
• DOI: 10.1111/j.1399-3011.1993.tb00135.x

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.