CNRS Institute of Analytical Sciences

Lyon, France

CNRS Institute of Analytical Sciences

Lyon, France
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Krimm I.,CNRS Institute of Analytical Sciences
ChemMedChem | Year: 2017

Allosteric drugs present many advantages over orthosteric drugs and are therefore an attractive approach in drug discovery, despite being highly challenging. First, the binding of ligands in protein allosteric pockets do not ensure an allosteric effect, and second, allosteric ligands can possess diverse modes of pharmacology even within a compound family. Herein we report a new method to: 1)detect allosteric communication between protein binding sites, and 2)compare the effect of allosteric ligands on the allosteric transitions of the protein target. The method, illustrated with glycogen phosphorylase, consists of comparing 1D saturation transfer difference (STD) NMR spectra of a molecular spy (here fragments) in the absence and presence of allosteric ligands. The modification of the STD NMR spectrum of the fragment indicates whether the protein dynamics/conformations have been changed in the presence of the allosteric modulator, thereby highlighting allosteric coupling between the binding pocket of the reference compound (in this case the fragment) and the allosteric pocket. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Knight M.J.,CNRS Institute of Analytical Sciences | Felli I.C.,University of Florence | Pierattelli R.,University of Florence | Emsley L.,CNRS Institute of Analytical Sciences | Pintacuda G.,CNRS Institute of Analytical Sciences
Accounts of Chemical Research | Year: 2013

Metal ions are ubiquitous in biochemical and cellular processes. Since many metal ions are paramagnetic due to the presence of unpaired electrons, paramagnetic molecules are an important class of targets for research in structural biology and related fields. Today, NMR spectroscopy plays a central role in the investigation of the structure and chemical properties of paramagnetic metalloproteins, linking the observed paramagnetic phenomena directly to electronic and molecular structure.A major step forward in the study of proteins by solid-state NMR came with the advent of ultrafast magic angle spinning (MAS) and the ability to use 1H detection. Combined, these techniques have allowed investigators to observe nuclei that previously were invisible in highly paramagnetic metalloproteins. In addition, these techniques have enabled quantitative site-specific measurement of a variety of long-range paramagnetic effects. Instead of limiting solid-state NMR studies of biological systems, paramagnetism provides an information-rich phenomenon that can be exploited in these studies.This Account emphasizes state-of-the-art methods and applications of solid-state NMR in paramagnetic systems in biological chemistry. In particular, we discuss the use of ultrafast MAS and 1H-detection in perdeuterated paramagnetic metalloproteins. Current methodology allows us to determine the structure and dynamics of metalloenzymes, and, as an example, we describe solid-state NMR studies of microcrystalline superoxide dismutase, a 32 kDa dimer. Data were acquired with remarkably short times, and these experiments required only a few milligrams of sample. © 2013 American Chemical Society.

Polotsky A.A.,RAS Institute of Macromolecular Compounds | Plamper F.A.,RWTH Aachen | Borisov O.V.,CNRS Institute of Analytical Sciences
Macromolecules | Year: 2013

We present a theory of a conformational collapse-to-swelling transition that occurs in aqueous dispersions of multiresponsive (pH- and thermoresponsive) microgels upon variation of ionic strength, temperature, or pH. Our theory is based on osmotic balance arguments and explicitly accounts for ionization equilibrium inside microgel partices. The theory predicts complex patterns in the dependence of the microgel particle dimensions on the control parameters: An increase in temperature leads to worsening of the solvent quality for the gel forming LCST-polymers and to concomitant decrease in the dimensions of the gel particles. This collapse of the gel particles provoked by an increase in temperature occurs either smoothly (at high or low ionic strength), or may exhibit a jump-wise character at intermediate ionic strength. The theory further predicts that the degree of swelling of microgel particles varies nonmonotonously and exhibits a maximum as a function of salt concentration at a pH close to the pK. This nonmonotonous variation of the particle dimensions occurs continuously at temperatures below or slightly above LCST (good or marginal poor solvent strength conditions, respectively), whereas at higher temperatures the jump-wise swelling of the gel particles is followed by either continuous or jump-wise collapse induced by progressive increase in the salt concentration. A decrease/increase in pH leads to deswelling of the weak polyacid/polybase gel particles, which occurs smoothly at temperatures below LCST, but may exhibit a discontinuity above LCST. These theoretical predictions can be used for design of smart stimuli-responsive microgels. © 2013 American Chemical Society.

Karamanis P.,CNRS Institute of Analytical Sciences | Pouchan C.,CNRS Institute of Analytical Sciences
Journal of Physical Chemistry C | Year: 2013

A study about the size-dependence of the hyperpolarizability-enhancement observed in metal-functionalized finite graphene species is presented. The reported ab initio and density functional results suggest that edge-passivation of graphene fragments with metallic agents (in this case Li) triggers an impressive enhancement of the second hyperpolarizability at the static limit. However, such a trend holds only in small graphene-type fragments. Strong evidence is provided showing that the specific effect drastically weakens with increasing the size of the graphene fragments regardless of their shape. The observed hyperpolarizability-enhancement in small systems and its severe decrease with increasing the size of the graphene species is qualitatively explained in terms of their charge transfer polarization mechanism. © 2013 American Chemical Society.

Karamanis P.,CNRS Institute of Analytical Sciences | Otero N.,CNRS Institute of Analytical Sciences | Pouchan C.,CNRS Institute of Analytical Sciences
Journal of the American Chemical Society | Year: 2014

In an attempt to diversify the options in designing graphene-based systems bearing large second order nonlinear optical (NLO) responses of octupolar and/or dipolar character, the subject of the quadratic NLO properties of hybrid boron nitride (BN) graphene flakes is opened up. State of the art ab initio and density functional theory methods applied on a toolbox of book-text octupolar and arbitrary dipolar planar hybrid h-BN-graphene nanosized systems reveal that by confining finite h-BN sections in the internal network of graphene, the capacity of the π-electron network of graphene species in delivering giant second order NLO responses could be fully exploited. Configuration interaction (CIS) and time-dependent density functional (TD) computations, within the sum-overstate (SOS) perturbational approach, expose that the prevailing (hyper)polarization mechanism, lying under the sizable computed octupolar hyperpolarizabilities, is fueled by alternating positive and negative atomic charges located in the internal part of the hybrid flakes, and more precisely at the BN/graphene intersections. This type of charge transfer mechanism distinguishes, in fact, the elemental graphene dipoles/octupoles we report here from other conventional NLO dipoles or octupoles. More interestingly, it is shown that by controlling the shape, size, and covering area of the h-BN domain (or domains), one can effectively regulate "à volonté" both the magnitudes and types of the second order NLO responses switching from dipolar to octupolar and vice versa. Especially in the context of the latter class of NLO properties, this communication brings into surface novel, graphene-based, octupolar planar or quasiplanar motifs. The take home message of this communication is summarized as follows: When the right BN segment is incorporated in the right section of the right graphene flake, systems of giant quadratic NLO octupolar and/or dipolar responses may emerge. © 2014 American Chemical Society.

Peysson W.,CNRS Institute of Analytical Sciences | Vulliet E.,CNRS Institute of Analytical Sciences
Journal of Chromatography A | Year: 2013

The aim of this study was to develop an analytical method for the analysis of a wide range of hormonal steroids and pharmaceutical compounds in sewage sludge. Thus, 136 substances were selected, including 119 pharmaceuticals and 17 hormonal steroids. An innovative sample preparation procedure based on the quick, easy, cheap, effective, rugged and safe (QuEChERS) method was developed. The analysis was then performed using liquid chromatography coupled with time-of-flight mass spectrometry. This analytical procedure was validated by evaluating the specificity, quadratic curve fitting, recovery, reproducibility and limits of detection and quantification. The method allows the analysis of the majority of the target compounds with limits of detection ranging from 1. ng/g to 2500. ng/g, depending on the nature of the substance. The protocol was then successfully applied to various types of sludge (limed, digested, dried, liquid and composted) collected in several sewage works in France. Among the target compounds, 34 were quantified at levels up to 6000. ng/g. Among the most commonly detected pharmaceuticals were the antiemetic domperidone (mean concentration 769. ng/g) and the antiepileptic lamotrigine (mean concentration 31. ng/g) whose presence had, to our knowledge, never been shown in sludge. © 2013 Elsevier B.V.

In this second paper of a two-part series, on-line RPLC × HILIC is compared to on-line RPLC × RPLC through the separation of peptides. Our choices regarding the conditions are discussed. Injection effects and overloading effects are evaluated in both configurations. It is shown that whereas large volumes can be injected in the second dimension in RPLC × RPLC under HT-UHPLC conditions (>20% of the column dead volume), even small injection volumes (8% of the column the dead volume) have a detrimental effect on peak shapes in RPLC × HILIC. Advantages and limits of the two 2D-systems are compared through the 2D-separation of a tryptic digest of three proteins. A ten-fold gain in analysis time along with a significant gain in peak capacity are obtained with both systems compared to the most efficient one-dimensional separation of peptides recently published. © 2013 Elsevier B.V.

Krimm I.,CNRS Institute of Analytical Sciences
MedChemComm | Year: 2012

In the fragment-based drug design approach, methods for rapid identification of the ligand-binding site are essential. The INPHARMA experiment, a ligand-observed NMR experiment based on the nuclear Overhauser effect, is tested here with fragment-like molecules and the glycogen phosphorylase enzyme that contain multiple binding sites. The results illustrate the potential of the method for the FBDD process and demonstrate that the INPHARMA experiment is particularly useful to study the binding specificity of the fragments and to assess the ligand binding mode in the presence of a reference ligand. © 2012 The Royal Society of Chemistry.

Epov V.N.,CNRS Institute of Analytical Sciences
Physical Chemistry Chemical Physics | Year: 2011

A novel approach is suggested to investigate the mechanisms of chemical complexation reactions based on the results of Fujii with co-workers; they have experimentally observed that several metals and metalloids demonstrate mass-independent isotope fractionation during the reactions with the DC18C6 crown ether using solvent-solvent extraction. In this manuscript, the isotope fractionation caused by the magnetic isotope effect is used to understand the mechanisms of chemical exchange reactions. Due to the rule that reactions are allowed for certain electron spin states, and forbidden for others, magnetic isotopes show chemical anomalies during these reactions. Mass-independent fractionation is suggested to take place due to the hyperfine interaction of the nuclear spin with the electron spin of the intermediate product. Moreover, the sign of the mass-independent fractionation is found to be dependent on the element and its species, which is also explained by the magnetic isotope effect. For example, highly negative mass-independent isotope fractionation of magnetic isotopes was observed for reactions of DC18C6 with SnCl2 species and with several Ru(iii) chloro-species, and highly positive for reactions of this ether with TeCl6 2-, and with several Cd(ii) and Pd(ii) species. The atomic radius of an element is also a critical parameter for the reaction with crown ether, particularly the element ions with [Kr]4d n5sm electron shell fits the best with the DC18C6 crown ring. It is demonstrated that the magnetic isotope effect in combination with the theory of orbital hybridization can help to understand the mechanism of complexation reactions. The suggested approach is also applied to explain previously published mass-independent fractionation of Hg isotopes in other types of chemical exchange reactions. © the Owner Societies 2011.

Vulliet E.,CNRS Institute of Analytical Sciences | Cren-Olive C.,CNRS Institute of Analytical Sciences
Environmental Pollution | Year: 2011

As part of a regional screening to evaluate the risk, for the health of populations, to certain classes of emerging substances, several families of pharmaceuticals and hormones were looked for in waters intended to drinking. Thus, 52 substances were investigated in 71 surface waters and 70 groundwaters. Results indicate that no water was free of pollutants, regardless of its origin (surface or groundwater) and the season of collect. The pharmaceuticals most frequently detected and with the highest concentration levels were salicylic acid, carbamazepine and acetaminophen. Among hormones, testosterone, androstenedione and progesterone were detected in almost all the samples. Globally the groundwaters were less contaminated than surface waters in regards pharmaceuticals frequencies and levels. On the other side, androgens and progestagens were present with comparable frequencies and levels in both compartments. The risk linked to the presence of these substances on human health is discussed. © 2010 Published by Elsevier Ltd.

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