title: Phosphonamidates as transition-state analogue inhibitors of thermolysin.
abstract: Six phosphorus-containing peptide analogues of the form Cbz-NHCH2PO2--L-Leu-Y (Y = D-Ala, NH2, Gly, L-Phe, L-Ala, L-Leu) have been prepared and evaluated as inhibitors of thermolysin. The Ki values for these compounds range from 1.7 microM to 9.1 nM and correlate well with the Km/kcat values for the corresponding peptide substrates [Morihara, K., & Tsuzuki, H. (1970) Eur. J. Biochem. 15, 374-380] but not with the Km values alone. The correlation noted between inhibitor Ki and substrate Km/kcat is the most extensive one of this type, providing strong evidence that the phosphonamidates are transition-state analogues and not simply multisubstrate ground-state analogues. Cbz-NH2CH2PO2--L-Leu-L-Leu (Ki = 9.1 nM) is the most potent inhibitor yet reported for thermolysin.
mesh_terms: D007700:Kinetics; D008433:Mathematics; D009842:Oligopeptides / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013820:Thermolysin / Q000037:antagonists & inhibitors*
chemical_list: D009842:Oligopeptides; D009943:Organophosphorus Compounds; D013820:Thermolysin