ABSTRACT
Endo peptidyl epoxides, in which the central epoxidic moiety replaces the scissile amide bond of a P(3)-P(3)' peptide, were designed as cysteine proteases inhibitors. The additional P'-S' interactions, relative to those of an exo peptidyl epoxide of the same P(3)-P(1) sequence, significantly improved affinity to the enzymes papain and cathepsin B, but also changed the mode of inhibition from active-site directed inactivation to reversible competitive inhibition. Computational models rationalize the binding affinity and the inhibition mechanism.
Subject(s)
Cysteine Proteinase Inhibitors/pharmacology , Epoxy Compounds/pharmacology , Peptides/pharmacology , Catalytic Domain , Cathepsin B/chemistry , Cathepsin B/metabolism , Cysteine Proteinase Inhibitors/chemistry , Epoxy Compounds/chemistry , Papain/chemistry , Papain/metabolism , Peptides/chemistry , Protein Conformation , Structure-Activity RelationshipABSTRACT
A transition-state analogue inhibitor that covalently reversibly binds to an enzyme formally consists of two parts: the chemical site, CS and the recognition site, RS. We have experimentally and theoretically demonstrated that the trend of binding affinity in a series of isoselective inhibitors (with identical RS and different CS fragments) depends mainly on their CS fragments. Isoselective inhibitors have the same affinity trend toward different enzymes of the same family with a common catalytic mechanism. Thus, very good correlation between experimentally determined and theoretically calculated Ki values was demonstrated. A practical outcome is the application of the described method as a tool for an expert analysis in virtual screening of inhibitor libraries and in the design of new enzyme inhibitors.
Subject(s)
Enzyme Inhibitors/metabolism , Binding Sites , Enzyme Inhibitors/chemistry , Magnetic Resonance Spectroscopy , Mass Spectrometry , ThermodynamicsABSTRACT
Magnetically responsive COOH-polydicarbazole-magnetite nanocomposites have been prepared by chemical oxidation of three COOH-dicarbazole monomers and - in the presence of magnetite nanoparticles. These functionalized nanoparticles have been tested for DNA hybridization experiments.