MNDO study of the mechanism of the inhibition of cysteine proteinases by diazomethyl ketones

• Published in: European biophysics journal Vol. 21; no. 3; pp. 217 - 222
• Main Authors: TARNOWSKA, M, OLDZIEJ, S, LIWA, A, KANIA, P, KASPRZYKOWSKI, F, GRZONKA, Z
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.07.1992
• Subjects: Biological and medical sciences; Chemical Phenomena; Chemistry, Physical; Cysteine Proteinase Inhibitors - chemistry; Cysteine Proteinase Inhibitors - pharmacology; Diazomethane - analogs & derivatives; Diazomethane - chemistry; Diazomethane - pharmacology; Fundamental and applied biological sciences. Psychology; Molecular biophysics; Molecular Structure; Structure in molecular biology; Cysteine; MNDO method; Enzyme; Quantum mechanics; Proteinase; Reaction path; Enzyme inhibitor; Models; Mechanism of action; Ketone; Nucleophile
• ISSN: 0175-7571; 1432-1017
• DOI: 10.1007/BF00196766

Diazomethyl ketones are one of the most effective irreversible inhibitors of cysteine proteinases and are therefore very important in drug design. In the present study a mechanism of inactivation is proposed based on the results of model MNDO calculations of the possible pathways. It was found that the mercaptide nucleophile, on approaching the carbonyl carbon as in the catalytic reaction path, binds to the inner diazo nitrogen. The intermediate thus formed can rearrange giving a stable product, beta-thioketone, and molecular nitrogen, with a considerable energy gain. The energy barrier to this process is equal to 36.9 kcal/mol, and corresponds to a pyramidal transition state with the vertex at the methylene carbon and the base formed by the carbonyl, thiol, and diazo groups. The energy barrier can be lowered on deprotonation of the intermediate. Based on the results obtained it was concluded that good irreversible inhibitors of cysteine proteases must fulfil two structural requirements: i) the dimensions and charge distribution must be similar to those of the peptide bond and ii) a second electrophilic center must be present in the neighbourhood of the carbonyl carbon. These are requirements which are satisfied by other strong cysteine proteinase inhibitors: beta-chloroketones and beta-ketooxiranes.