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Afin de mieux comprendre les mécanismes régissant les relations structure-activité au sein de systèmes à visée thérapeutique, des calculs de chimie quantique et de dynamique moléculaire sont menés en complément des synthèses effectuées au laboratoire.
Theoretical and experimental studies of chitin nanocrystals treated with ionic liquid or deep eutectic solvent to afford nanochitosan sheets |
Mass Spectrometry, Ion Mobility Separation and Molecular Modelling: A Powerful Combination for the Structural Characterisation of Substituted Cyclodextrins Mixtures |
Copper-uptake mediated by an ecofriendly zwitterionic ionic liquid: A new challenge for a cleaner bioeconomy |
Fundamental insight into the interaction between a lithium salt and an inorganic filler for ion mobility using a synergic theoretical-experimental approach |
Cyclodextrin complexation studies as the first step for repurposing of chlorpromazine |
New biobased-zwitterionic ionic liquids: efficiency and biocompatibility for the development of sustainable biorefinery processes |
Ironing out pyoverdine’s chromophore structure: serendipity or design? |
Impact of iron coordination isomerism on pyoverdine recognition by the FpvA membrane transporter of Pseudomonas aeruginosa |
The origin of the stereoselective alkylation of 3-substituted-2-oxopiperazines: A computational investigation |
Probing the common alkali metal affinity of native and variously methylated [small beta]-cyclodextrins by combining electrospray-tandem mass spectrometry and molecular modeling |
Selectivity of pyoverdine recognition by the FpvA receptor of Pseudomonas aeruginosa from molecular dynamics simulations |
Diesterification of 3-[(β-Cyclodextrinyl)succinamido]propane-1,2-diol Catalysed by Lipase: Diastereoselectivity or Tridimensional Substrate Specificity? |
Chitin nanocrystals have gained growing interest due to their many excellent properties, however the higher crystallinity of these nano-rod-shaped particles is a major hindering factor in preparation of nanochitosans with low degree of acetylation (DA). Here we studied the effect of the ionic liquid 1-ethyl-3-methylimidazolium acetate (IL) and deep eutectic solvent (choline chloride:lactic acid) (DES) pretreatments of chitin nanocrystals (NCChits) before the deacetylation step using both experimental and theoretical approaches. The results showed that the ionic liquid pretreatment was able to partially disrupt the crystalline structure leading to a lower DA (18.2 %) after two cycles of deacetylation reaction. DES pretreatment, however, was unable to disturb the intra- and intermolecular hydrogen bonds, resulting in a DA of 73.6 % similar to that of unpretreated chitin nanocrystals (73.2 %). SEM images of chitin nanocrystals pretreated with ionic liquid showed that the crystals can rearrange into sheets. Molecular simulations reveal the detailed mechanism of chitin nanocrystal dissociation, in which the combination of a net molecular charge and hydrogen-bonding groups on a single scaffold (as is the case for [C2mim] and [OAc]) plays a paramount role. These results can open the way to afford controlled nanochitosan sheets from chitin nanocrystals.
This study aims to investigate the ability of an imidazolium biobased Zwitterionic Ionic Liquids (ZILs) in enhancing the phytoavailability of copper from garden (G) and vineyard (V) soils using the model plant ryegrass. Uncontaminated and artificially contaminated CuSO4 soils, unamended and ZIL-amended soil modalities were designed. The copper/ZIL molar ratio (1/4) introduced was rationally established based on molecular modeling and on the maximal copper concentration in artificially contaminated soil. Higher accumulation of copper in the shoots was detected for the uncontaminated and copper contaminated ZIL amended V soils (18.9 and 23.3 mg.kg−1, respectively) contrary to G soils together with a ZIL concentration of around 3% w/w detected by LC-MS analyses. These data evidenced a Cu-accumulation improvement of 38 and 66% compared to non-amended V soils (13.6 and 13.9 mg.kg−1 respectively). ZIL would be mainly present under Cu(II)-ZIL4 complexes in the shoots. The impact on the chemical composition of shoot were also studied. The results show that depending on the soils modalitity, the presence of free copper and/or ZIL led to different chemical compositions in lignin and monomeric sugar contents. In the biorefinery context, performances of enzymatic hydrolysis of shoots were also related to the presence of both ZIL and copper under free or complex forms. Ecotoxicity assessment of the vineyard soil samples indicated that the quantity of copper and ZIL remaining in the soils had no significant toxicity. ZIL amendment in a copper-contaminated soil was demonstrated as being a promising way to promote the valorization of phytoremediation plants.
The present paper aims at providing a fundamental insight into the interaction between a lithium salt and an inorganic filler in a perspective of lithium mobility. Through a synergistic approach, coupling experimental results and molecular dynamics simulations, the influence of the surface chemical state of the nanosilica Stöber-type on the dissociation of LiTFSI and its impact on the lithium conduction properties are studied. For this purpose, the surface modification of silica nanoparticles was performed by different methods such as calcination, lithiation and capping with organosilane. The impact of the surface modification on the dissociation of the lithium salt is further investigated by electrochemical impedance spectroscopy after impregnation of the material with a defined amount of lithium salt. The combined experimental and in silico analyses of the results, performed for the first time on such systems, allow a detailed understanding of the interaction between the salt and the support and should prove itself useful for the future design of hybrid polymer electrolytes in new generation batteries.
The antipsychotic drug chlorpromazine (CPZ) has potential for the treatment of acute myeloid leukemia, if central nervous system side-effects resulting from its passage through the blood–brain barrier can be prevented. A robust drug delivery system for repurposed CPZ would be drug-in-cyclodextrin-in-liposome that would redirect the drug away from the brain while avoiding premature release in the circulation. As a first step, CPZ complexation with cyclodextrin (CD) has been studied. The stoichiometry, binding constant, enthalpy, and entropy of complex formation between CPZ and a panel of CDs was investigated by isothermal titration calorimetry (ITC). All the tested CDs were able to include CPZ, in the form of 1:1, 1:2 or a mixture of 1:1 and 1:2 complexes. In particular, a substituted γ-CD, sugammadex (the octasodium salt of octakis(6-deoxy-6-S-(2-carboxyethyl)-6-thio)cyclomaltooctaose), formed exclusively 1:2 complexes with an extremely high association constant of 6.37 × 109 M−2. Complexes were further characterized by heat capacity changes, one- and two-dimensional (ROESY) nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics simulations. Finally, protection of CPZ against photodegradation by CDs was assessed. This was accelerated rather than reduced by complexation with CD. Altogether these results provide a molecular basis for the use of CD in delayed release formulations for CPZ.
A new family of biobased-zwitterionic ionic liquids (ZILs) have been synthesized starting from the renewable resource l-histidine natural amino acid and varying the lengths of the alkyl chains. These ZIL derivatives were firstly studied for their biocompatibility with different microorganisms including bacteria, molds and yeast. The obtained MIC values indicated that all the microorganisms were 5 to 25 times more tolerant to ZIL derivatives than the robust 1-ethyl-3-methylimidazolium acetate [C2mim][OAc] used as a reference. Modeling studies also revealed that the presence of the cation and the anion on the same skeleton together with the length of the N-alkyl chain would govern the biocompatibility of these neoteric solvents. Among the different synthesized ZILs, the N,N′-diethyl derivative has been demonstrated to be a suitable eco-alternative to the classically used [C2mim][OAc] for efficient pretreatment of harwood sawdust leading to a significant improvement of enzymatic saccharification. In addition, with up to a 5% w/v concentration in the culture medium, ZILs did not induce deleterious effects on fermentative yeast growth nor ethanol production.
Pyoverdines are Pseudomonas aeruginosa’s primary siderophores. These molecules, composed of a fluorescent chromophore attached to a peptide chain of 6–14 amino acids, are synthesized by the bacterium to scavenge iron (essential to its survival and growth) from its environment. Hijacking the siderophore pathway to use pyoverdine–antibiotic compounds in a Trojan horse approach has shown promise but remains very challenging because of the synthetic efforts involved. Indeed, both possible approaches (grafting an antibiotic on pyoverdine harvested from Pseudomonas or designing a total synthesis route) are costly, time-consuming and low-yield tasks. Designing comparatively simple analogs featuring the salient properties of the original siderophore is thus crucial for the conception of novel antibiotics to fight bacterial resistance. In this work, we focus on the replacement of the pyoverdine chromophore, a major roadblock on the synthetic pathway. We propose three simpler analogs and evaluate their ability to complex iron and interact with the FpvA transporter using molecular modeling techniques. Based on these results, we discuss the role of the native chromophore’s main features (polycyclicity, positive charge, flexibility) on pyoverdine’s ability to bind iron and be recognized by membrane transporter FpvA and propose guidelines for the design of effective synthetic siderophores.
Pyoverdines, the primary siderophores of Pseudomonas bacteria, scavenge the iron essential to bacterial life in the outside medium and transport it back into the periplasm. Despite their relative simplicity, pyoverdines feature remarkably flexible recognition characteristics whose origins at the atomistic level remain only partially understood: the ability to bind other metals than ferric iron, the capacity of outer membrane transporters to recognize and internalize noncognate pyoverdines from other pseudomonads... One of the less examined factors behind this polymorphic recognition lies in the ability for pyoverdines to bind iron with two distinct chiralities, at the cost of a conformational switch. Herein, we use free energy simulations to study how the stereochemistry of the iron chelating groups influences the structure and dynamics of two common pyoverdines and impacts their recognition by the FpvA membrane transporter of P. aeruginosa. We show that conformational preferences for one metal binding chirality over the other, observed in solution depending on the nature of the pyoverdine, are canceled out by the FpvA transporter, which recognizes both chiralities equally well for both pyoverdines under study. However, FpvA discriminates between pyoverdines by altering the kinetics of stereoisomer interconversion. We present structural causes of this intriguing recognition mechanism and discuss its possible significance in the context of the competitive scavenging of iron.
2-Oxopiperazines and their derivatives are important pharmacophores found in numerous bioactive products. The potency of these compounds depends on the nature and/or position of their substituent(s) as well as on their chirality. Hence, it is important to develop, control and optimize synthetic routes leading to enantiomerically pure substituted 2-oxopiperazines. In this work we report on the origin of this stereoselectivity, upon alkylation of 2-oxopiperazines at position C3, studied by means of quantum chemistry calculations. Indeed, this alkylation with methyl chloride is predicted to afford mainly the exo product with a 98:2 ratio. To this purpose, we model the reaction path leading to both enantiomers by scrutinizing the structures and energetics of the pre-reaction complexes, the transition states and the post-reaction complexes. The computational results are in good agreement with the experimental observations, and provide valuable insights into the origins of this specificity. From the conformational analysis of the piperazine ring and of intramolecular interaction patterns, we show that the enantiofacial discrimination is achieved by a subtle balance between sterical hindrance and control of the conformation of the piperazine ring.
The Gram-negative bacterium Pseudomonas aeruginosa, a ubiquitous human opportunistic pathogen, has developed resistances to multiple antibiotics. It uses its primary native siderophore, pyoverdine, to scavenge the iron essential to its growth in the outside medium and transport it back into its cytoplasm. The FpvA receptor on the bacterial outer membrane recognizes and internalizes pyoverdine bearing its iron payload, but can also bind pyoverdines from other Pseudomonads or synthetic analogues. Pyoverdine derivatives could therefore be used as vectors to deliver antibiotics into the bacterium. In this study, we use molecular dynamics and free energy calculations to characterize the mechanisms and thermodynamics of the recognition of the native pyoverdines of P. aeruginosa and P. fluorescens by FpvA. Based on these results, we delineate the features that pyoverdines with high affinity for FpvA should possess. In particular, we show that (i) the dynamics and interaction of the unbound pyoverdines with water should be optimized with equal care as the interface contacts in the complex with FpvA; (ii) the C-terminal extremity of the pyoverdine chain, which appears to play no role in the bound complex, is involved in the intermediate stages of recognition; and (iii) the length and cyclicity of the pyoverdine chain can be used to fine-tune the kinetics of the recognition mechanism.