Catherine Michaux

Dual inhibition of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) as a new strategy to provide safer non-steroidal anti-inflammatory drugs

Dual COX/5-LOX (cyclooxygenase/5-lipoxygenase) inhibitors constitute a valuable alternative to classical non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors for the treatment of inflammatory diseases. Indeed, these latter present diverse side effects, which are reduced or absent in dual-acting agents. In this review, COX and 5-LOX pathways are first described in order to highlight the therapeutic interest of designing such compounds. Various structural families of dual inhibitors are illustrated.

Effects of hydration on the proton transfer mechanism in the adenine-thymine base pair.

We report the first density functional study of water catalytic effect in the double proton transfer (DPT) taking place in the adenine-thymine (AT) base pair. To gain more insight regarding the accuracy of several theoretical methods, the ability of various functionals and models for describing the geometry of this system has first been checked. According to our results, BP86/6-311++G(d,p) is the best option for describing the solvation effects in AT when applied to a two-water-molecule-featuring model. The two possible mechanisms for DPT in solution are explored: in the first one, water molecules only remain passive elements, whereas in the second one they are directly included in the reaction path. For the noncatalyzed mechanism, the stable structures constitute the canonical form of the base pair and the first proton transfer product. Nevertheless, by involving the two water molecules in the reaction, we found three stable species: canonical base pair, first proton transfer product, and double proton transfer product. Although the thermodynamic analysis confirms that AT does not contribute to spontaneous mutation through proton transfer catalyzed by surrounding water, our results suggest that microhydration may play a crucial role for DPT reaction in others DNA or RNA basis pair.

Synthesis and activity of a new methoxytetrahydropyran derivative as dual cyclooxygenase-2/5-lipoxygenase inhibitor.

Dual COX-2/5-LO inhibitors are described as potential new therapeutic agents for inflammatory diseases. A surprisingly potent effect of a 5-LO pharmacophoric group on the COX-2 inhibition is presented as well as pharmacological in vitro and in vivo results.

Intermolecular Proton Transfer in Microhydrated Guanine−Cytosine Base Pairs: a New Mechanism for Spontaneous Mutation in DNA

Accurate calculations of the double proton transfer (DPT) in the adenine-thymine base pair (AT) were presented in a previous work [J. Phys. Chem. A 2009, 113, 7892.] where we demonstrated that the mechanism of the reaction in solution is strongly affected by surrounding water. Here we extend our methodology to the guanine-cytosine base pair (GC), for which it turns out that the proton transfer in the gas phase is a synchronous concerted mechanism. The O(G)-H-N(C) hydrogen bond strength emerges as the key parameter in this process, to the extent that complete transfer takes place by means of this hydrogen bond. Since the main effect of the molecular environment is precisely to weaken this bond, the direct proton transfer is not possible in solution, and thus the tautomeric equilibrium must be assisted by surrounding water molecules in an asynchronous concerted mechanism. This result demonstrates that water plays a crucial role in proton reactions. It does not act as a passive element but actually catalyzes the DPT.

Structural approach for COX-2 inhibition

The design of selective COX-2 inhibitors is a new approach to obtain potent, anti-inflammatory drugs but with less side effects. Several families of such inhibitors were reported in literature. In this review, the drug design processes used to understand their binding mode and the origin of selectivity of these compounds are described.

Microhydration of Protonated Glycine: An ab initio Family Tree

The incremental hydration of the glycine cation is investigated using an ab initio approach fully correcting for basis set superposition errors and explicitly incorporating electron-correlation effects. Structures with zero to four surrounding water molecules have been determined. It is demonstrated that the successive aggregates follow a Darwinian family tree, the most stable complexes systematically belonging to the same branch of the tree. In strong contrast with neutral glycine, the direct hydrogen bonding to the glycine cation is favored over bridging water structures. The agreement between experimental and theoretical hydration enthalpies and Gibbs free energies is impressive, as ab initio estimates almost systematically fit the experimental error bars. For GlyH(+)-(H2O) and GlyH(+)-(H2O)3, we show that two structures are generated by the experimental setup. The present approach also resolves most of the previous theory/experiment discrepancies and provides patterns for the evolution of the vibrational spectra: a decrease of the hydrogen-bond stretching frequency indicating second-shell water molecules. Additionally, the impact of bulk solvent solvation is investigated, as four discrete water molecules still do not fully hydrate the protonated glycine.

Crystal structure of a cold-adapted class C beta-lactamase

In this study, the crystal structure of a class C β‐lactamase from a psychrophilic organism, Pseudomonas fluorescens, has been refined to 2.2 Å resolution. It is one of the few solved crystal structures of psychrophilic proteins. The structure was compared with those of homologous mesophilic enzymes and of another, modeled, psychrophilic protein. The elucidation of the 3D structure of this enzyme provides additional insights into the features involved in cold adaptation. Structure comparison of the psychrophilic and mesophilic β‐lactamases shows that electrostatics seems to play a major role in low‐temperature adaptation, with a lower total number of ionic interactions for cold enzymes. The psychrophilic enzymes are also characterized by a decreased number of hydrogen bonds, a lower content of prolines, and a lower percentage of arginines in comparison with lysines. All these features make the structure more flexible so that the enzyme can behave as an efficient catalyst at low temperatures.

First crystal structure of an endo-inulinase, INU2, from Aspergillus ficuum: discovery of an extra-pocket in the catalytic domain responsible for its endo-activity.

Endo-inulinase is a member of glycosidase hydrolase family 32 (GH32) degrading fructans of the inulin type with an endo-cleavage mode and is an important class of industrial enzyme. In the present study, we report the first crystal structure of an endo-inulinase, INU2, from Aspergillus ficuum at 1.5 Å. It was solved by molecular replacement with the structure of exo-inulinase as search model. The 3D structure presents a bimodular arrangement common to other GH32 enzymes: a N-terminal 5-fold β-propeller catalytic domain with four β-sheets and a C-terminal β-sandwich domain organized in two β-sheets with five β-strands. The structural analysis and comparison with other GH32 enzymes reveal the presence of an extra pocket in the INU2 catalytic site, formed by two loops and the conserved motif W-M(I)-N-D(E)-P-N-G. This cavity would explain the endo-activity of the enzyme, the critical role of Trp40 and particularly the cleavage at the third unit of the inulin(-like) substrates. Crystal structure at 2.1 Å of INU2 complexed with fructosyl molecules, experimental digestion data and molecular modelling studies support these hypotheses.

Theoretical Investigation of the Geometries and UV−vis Spectra of Poly(l-glutamic acid) Featuring a Photochromic Azobenzene Side Chain

The geometries and UV-vis spectra of azobenzene dyes grafted as a side chain on poly(l-glutamic acid) have been investigated using a combination of quantum mechanics/molecular mechanics (QM/MM) and time-dependent density functional theory (TD-DFT) methods at the TD-PBE0/6-311+G(d,p)//B3LYP/6-311G(d,p):Amber ff99 level of theory. The influence of the secondary structure of the polypeptide on the electronic properties of both the trans and cis conformations of azobenzene dyes has been studied. It turns out that the grafted dyes exhibit a red-shift of the π → π* absorption energies mainly due to the auxochromic shift induced by the peptidic group used to link the chromophoric unit to the polypeptide and that specific interactions between the glutamic side chain and the azobenzene moiety lead to a large blue-shift of the n → π* transition.

Design, synthesis and biological evaluation of a sulfonylcyanoguanidine as thromboxane A2 receptor antagonist and thromboxane synthase inhibitor.

The synthesis and the structure of N‐isopropyl‐N′‐[2‐(3′‐methylphenylamino)‐5‐nitrobenzenesulfonyl] urea (14) was drawn from two thromboxane A2 receptor antagonists structurally related to torasemide. Compound 14 showed an IC50 value of 22 nm for the thromboxane A2 (TXA2) receptor of human washed platelets. Compound 14 prevented platelet aggregation induced by arachidonic acid (0.6 mm) and U‐46619 (1 μm) with an IC50 value of 0.45 and 0.15 μm, respectively. Moreover, 14 relaxed the rat isolated aorta and guinea‐pig trachea precontracted by U‐46619, a TXA2 agonist. Its efficacy (IC50) was 20.4 and 5.47 nm, respectively. Finally, 14 (1 μm) completely inhibited TXA2 synthase of human platelets. The pKa value and the crystallographic data of 14 were determined and used to propose an interaction model between the TXA2 antagonists related to torasemide and their receptor.