Transition state analog

Transition state analogs (transition state analogues), are chemical compounds with a chemical structure that resembles the transition state of a substrate molecule in an enzyme-catalyzed chemical reaction. Enzymes interact with a substrate by means of strain or distortions, moving the substrate towards the transition state. Transition state analogs can be used as inhibitors in enzyme-catalyzed reactions by blocking the active site of the enzyme. Theory suggests that enzyme inhibitors which resembled the transition state structure would bind more tightly to the enzyme than the actual substrate. Examples of drugs that are transition state analog inhibitors include flu medications such as the neuraminidase inhibitor oseltamivir and the HIV protease inhibitors saquinavir in the treatment of AIDS. Transition state analogue The transition state of a structure can best be described in regards to statistical mechanics where the energies of bonds breaking and forming have an equa

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Enzyme catalysis is the increase in the rate of a process by a biological molecule, an "enzyme". Most enzymes are proteins, and most such processes are chemical reactions. Within the enzyme, generall

Enzymes (ˈɛnzaɪmz) are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the subst

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Applications of density functional theory-based methods in medicinal chemistry

Ursula Röthlisberger

A review. With the advances in genomics, proteomics and functional genomics new therapeutic targets to be tackled by medicinal chem. are expected. This article reviews applications of first principle methods to address medicinal chem. issue related to drug/target interactions. Two selected representative case studies involving therapeutically interesting targets are presented. The first case study presents how DFT can contribute to ameliorate scoring functions for drug screening in particular by enabling the discrimination between inhibitors and substrates. The second example shows the use of DFT within the framework of a QM/MM mixed approach for elucidating mechanisms of reaction. This approach allows defining the electronic state and structure of the reaction transition state whose knowledge is essential for designing potent and specific transition state analogs inhibitors. Finally, addressing the issue of other medicinal chem. related application of DFT we suggest that DFT has indeed the potentiality of becoming very important for challenging new issues presented to medicinal chem. in the post genomic era. [on SciFinder (R)]

2002

Reaction mechanism of caspases: Insights from QM/MM Car-Parrinello simulations

Ursula Röthlisberger

Caspases are fundamental targets for pharmaceutical interventions in a variety of diseases involving disregulated apoptosis. Here, we present a quantum mechanics/mol. mechanics Car-Parrinello study of key steps of the enzymic reaction for a representative member of this family, caspase-3. The hydrolysis of the acyl-enzyme complex is described at the d. functional (BLYP) level of theory while the protein frame and solvent are treated using the GROMOS96 force field. These calcns. show that the attack of the hydrolytic water mol. implies an activation free energy of .apprx.DFA ~ 19+-4 kcal/mol in good agreement with exptl. data and leads to a previously unrecognized gem-diol intermediate that can readily (DFA ~ 5+-3 kcal/mol) evolve to the enzyme products. Our findings assist in elucidating the striking difference in catalytic activity between caspases and other structurally well-characterized cysteine proteases (papains and cathepsins) and may help design novel transition-state analog inhibitors. [on SciFinder (R)]

2003

A comparative study of galactose oxidase and active site analogs based on QM/MM Car-Parrinello simulations

Paolo Carloni, Michele Parrinello, Ursula Röthlisberger

A parallel study of the radical copper enzyme galactose oxidase (GOase) and a low mol. wt. analog of the active site was performed with dynamic d. functional and mixed quantum-classical calcns. This combined approach enables a direct comparison of the properties of the biomimetic and the natural systems throughout the course of the catalytic reaction. In both cases, five essential forms of the catalytic cycle have been investigated: the resting state in its semi-reduced (catalytically inactive) and its oxidized (catalytically active) form, Asemi and Aox, resp.; a protonated intermediate B; the transition state for the rate-detg. hydrogen abstraction step C, and its product D. For A and B the electronic properties of the biomimetic compd. are qual. very similar to the ones of the natural target. However, in agreement with the exptl. obsd. difference in catalytic activity, the calcd. activation energy for the hydrogen abstraction step is distinctly lower for GOase (16 kcal/mol) than for the mimetic compd. (21 kcal/mol). The enzymic transition state is stabilized by a delocalization of the unpaired spin d. over the sulfur-modified equatorial tyrosine Tyr272, an effect that for geometric reasons is essentially absent in the biomimetic compd. Further differences between the mimic and its natural target concern the structure of the product of the abstraction step, which is characterized by a weakly coordinated aldehyde complex for the latter and a tightly bound linear complex for the former. [on SciFinder (R)]

2000

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Enzyme catalysis is the increase in the rate of a process by a biological molecule, an "enzyme". Most enzymes are proteins, and most such processes are chemical reactions. Within the enzyme, generall