Experimental methods have certain limits and there are times when nature briefly switches off the lights on scene to hide its tricks. One of these moments takes place during chemical reactions. All chemical reactions go through a sort of Limbo, a ghost-like stage between the initial reagents and the final product in which it is almost impossible to know experimentally what has occurred in the intermediate phase. A group of researchers from the Universitat Jaume I (UJI) of Castelló use techniques based on computational chemistry to theoretically model this unknown transition state and thus design compounds that either inhibit or enhance the action of biological catalysts.
A chemical reaction resembles the pass from one valley to another by way of a mountain. Valleys are stable areas, but if we attempt to go from one to the other, we need to cross an unstable point of maximum height along the way, that is, a hill. In the case of a chemical reaction, the initial and final molecules also have the features of stable structures that can be studied experimentally. To skip between them however, it is necessary to go through an unstable structure of maximum energy throughout the reaction, the hill of the chemical reaction, or in other words, its transition state.
This state is particularly interesting because biological catalysts or enzymes which accelerate chemical reactions taking place in living beings (from the transformation of food into energy to cell reproduction, among many others) do so by stabilising this unstable structure. Intervening in this transition state would allow us to stop or enhance a chemical reaction. However, this is so brief that it is impossible to know its structure in an experimental way. By means of theoretical simulations and the use of high-performance computers, researchers at the UJI have found out the way that certain chemical reactions follow, and have either suggested ways of blocking it, or proposed more efficient alternative routes.
“If we know the transition state structure, which is unstable by definition and, therefore, cannot be studied experimentally, we can then synthesise molecules that are similar to it yet chemically stable, which in other words is known as a transition state analogue”, explains Vicent Moliner, the person in charge of the research. The transition state analogue (TSA) is the molecular negative of the enzyme catalysing a certain reaction. This may then be used to block such enzyme action, by thus inhibiting an undesired chemical reaction from occurring.
“The development of this project is fundamental to improve the selectivity of drugs applied in chemical-therapeutic treatments. If we are able to know the structure of transition states in catalytic reactions involved, for example, in cell proliferation processes in tumours, we will be able to design drugs capable of stopping these reactions and preventing the spread of cancer”, explains Vicent Moliner. This principle can also be applied to other pathologies. “Among other systems, we are currently working with catechol-O-methyl transferase given its future applications in the treatment of degenerative diseases such as Parkinson’s disease. We are also working with HIV-1 IN, an enzyme that uses the HIV virus to replicate itself”, Moliner adds.
In the case of degenerative diseases, Moliner’s team has managed to define the structure of the transition state of a chemical reaction which is a key factor in the production of dopamine. The disequilibrium in the generation of this neurotransmitter is responsible for certain neurological diseases, such as Parkinson’s disease. “Knowing the structure of this reaction is a crucial step. We are now close to being able to suggest the synthesis of inhibitors that correct the disequilibrium of dopamine”, explains Vicent Moliner. The results have been published in several articles in the Journal of the American Chemical Society and in Chemical Society Reviews.
However, knowing the structure of chemical reactions is not only useful to block them, but also to propose biological catalysts for chemical reactions that we wish to accelerate. To this end, the TSA compound is introduced in a living system ( a rodent) to generate antibodies that will be macromolecules to complement TSA, that is, something like its photograph negative. Since antibodies are complementary to TSA, they can then be used as catalysts as they stabilise the transition state of the chemical reaction. These compounds are known as catalytic antibodies (CA).
“Nevertheless, catalytic antibodies that are generated so (germline CA) do not work very well as catalysts, so an improvement is sought for by means of selective mutations in the lab through trial and error tests (matured CA). However, this improvement is not very effective, and the work we have been carrying out in our group allows us to rationally determine what mutations should be tested in the lab to enhance the catalytic activity of CA”, Moliner points out. “These new molecules are particularly interesting in processes for which no catalyst exists to catalyse them, or for those processes in which the enzyme is not functioning properly”, Moliner indicates. These results have recently been published in the journal Angewandte Chemie.
Hugo Cerdà | alfa
A novel socio-ecological approach helps identifying suitable wolf habitats
17.02.2017 | Universität Zürich
New, ultra-flexible probes form reliable, scar-free integration with the brain
16.02.2017 | University of Texas at Austin
Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...
The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.
The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...
Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...
Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".
Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...
13.02.2017 | Event News
10.02.2017 | Event News
09.02.2017 | Event News
20.02.2017 | Power and Electrical Engineering
17.02.2017 | Medical Engineering
17.02.2017 | Medical Engineering