title: Assessment of a mechanism for reactive inhibition of carboxypeptidase A with QM/MM methods.
abstract: The mechanism for inhibition of carboxypeptidase A (CPA) by the two enantiomers of a reactive inhibitor, N-(2-chloroethyl)-N-methylphenylalanine, has been investigated using computational methods. Quantum mechanical and molecular mechanical (QM/MM) methods have been employed to find likely enzyme binding conformations by comparison with the observed rates of inactivation of the enzyme. The study has shown that the enzyme active site appears to be flexible enough to allow the nucleophilic deactivation reactions of both the (R) and (S) forms of a model of the inhibitor to be catalysed by the Zn(II) cofactor of CPA.
authors.affiliation: School of Chemistry, University of Manchester, Manchester M13 9PL, UK.
authors.forename: Lily
authors.initials: L
authors.lastname: Phoon
authors.forename: Neil A
authors.initials: NA
authors.lastname: Burton
mesh_terms: D001665:Binding Sites; D043422:Carboxypeptidases A / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D020134:Catalytic Domain; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry*; D007700:Kinetics; D008956:Models, Chemical; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry; D011487:Protein Conformation; D011789:Quantum Theory; D013237:Stereoisomerism; D015032:Zinc / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; C431768:N-(2-chloroethyl)-N-methylphenylalanine; D010649:Phenylalanine; D043422:Carboxypeptidases A; D015032:Zinc