Search results for "Transition state analog"
showing 7 items of 7 documents
Theozyme for antibody aldolases. Characterization of the transition-state analogueElectronic supplementary information (ESI) available: MP2/6-31G** e…
2003
A theozyme for antibody aldolases has been studied at the MP2/6-31G** computational level. Formation of two cooperative hydrogen-bonds between the acidic hydrogen atoms of the enamine and of a methanol molecule with the oxygen atom of the aldol acceptor markedly favors the C–C bond-formation associated with the aldol reaction. A comparative analysis of the geometry, the charge distribution and the shape of the molecular electrostatic potential of the transition structure (TS) with the covalent adduct, resulting from the reaction of methylamine and the β-diketone used as a hapten allows us to characterize the transition-state analogue (TSA) generated at immunization. This finding allows us t…
Enzymatic effects on reactant and transition states. The case of chalcone isomerase.
2007
Chalcone isomerase catalyzes the transformation of chalcone to naringerin as a part of flavonoid biosynthetic pathways. The global reaction takes place through a conformational change of the substrate followed by chemical reaction, being thus an excellent example to analyze current theories about enzyme catalysis. We here present a detailed theoretical study of the enzymatic action on the conformational pre-equilibria and on the chemical steps for two different substrates of this enzyme. Free-energy profiles are obtained in terms of potentials of mean force using hybrid quantum mechanics/molecular mechanics potentials. The role of the enzyme becomes clear when compared to the counterpart eq…
Using theozymes for designing transition-state analogs for the intramolecular aldol reaction of δ-diketones
2001
Two theozymes for the intramolecular aldol reaction of δ-diketones have been studied using ab initio methods. The presence of both acid/base residues favors several steps of the aldol reaction. The appropriate positioning of these residues can accelerate one of two diastereromeric reaction pathways, the catalyzed aldol reaction being highly stereoselective. Analysis of the geometrical parameters, charge distribution, and the shape of molecular electrostatic potential for the corresponding acid/base catalyzed transition structure allows us to design adequate transition-state analogs to favor a reactive channel of this intramolecular aldol reaction. © 2001 John Wiley & Sons, Inc. Int J Quant …
Toward very potent, non-covalent organophosphonate inhibitors of cathepsin C and related enzymes by 2-amino-1-hydroxy-alkanephosphonates dipeptides
2013
Cathepsins play an important role in several human disorders and therefore the design and synthesis of their inhibitors attracts considerable interest in current medicinal chemistry approaches. Due to the presence of a strong sulphydryl nucleophile in the active center of the cysteine type cathepsins, most strategies to date have yielded covalent inhibitors. Here we present a series of non-covalent β-amino-α-hydroxyalkanephosphonate dipeptidic inhibitors of cathepsin C, ranking amongst the best low-molecular weight inhibitors of this enzyme. Their binding modes determined by molecular modelling indicate that the hydroxymethyl fragment of the molecule, not the phosphonate moiety, acts as a t…
N-Benzyl Residues as the P1′ Substituents in Phosphorus-Containing Extended Transition State Analog Inhibitors of Metalloaminopeptidases
2020
Peptidyl enzyme inhibitors containing an internal aminomethylphosphinic bond system (P(O)(OH)-CH2-NH) can be termed extended transition state analogs by similarity to the corresponding phosphonamidates (P(O)(OH)-NH). Phosphonamidate pseudopeptides are broadly recognized as competitive mechanism-based inhibitors of metalloenzymes, mainly hydrolases. Their practical use is, however, limited by hydrolytic instability, which is particularly restricting for dipeptide analogs. Extension of phosphonamidates by addition of the methylene group produces a P-C-N system fully resistant in water conditions. In the current work, we present a versatile synthetic approach to such modified dipeptides, based…
A three-component Mannich-type condensation leading to phosphinic dipeptides—extended transition state analogue inhibitors of aminopeptidases
2011
Abstract N-Protected α-aminoalkylphosphinic acids bearing a P–H function were found to be novel practical building blocks in three-component condensations with formaldehyde and secondary amines (amino acids). Such Mannich-type N -phosphonomethylation is a common approach for phosphorus acid derived substrates and leads to multifunctional (phosphonic/amino/carboxylic) compounds of diverse relevance. The utility of this reaction was examined for construction, in a single synthetic step, of advanced phosphinic pseudodipeptides designed to act as extended transition state analogue inhibitors of selected aminopeptidases. Phosphinomethylation of primary amino acids was less efficient and yielded …
Designing a Transition State Analogue for the Disfavored Intramolecular Michael Addition of 2-(2-Hydroxyethyl)acrylate Esters
1999
The rate-determining steps for the intramolecular 1,2 and 1,4 addition reactions in basic medium of methyl 2-(2-hydroxyethyl)acrylate to give the corresponding γ-lactone and tetrahydrofuran, respec...