Structure-Based Identification of Inhibitors Disrupting the CD2-CD58 Interactions

International audienceThe immune system has very intricate mechanisms of fighting against the invading infections which are accomplished by a sequential event of molecular interactions in the body. One of the crucial phenomena in this process is the recognition of T-cells by the antigen-presenting cells (APCs), which is initiated by the rapid interaction between both cell surface receptors, i.e., CD2 located on T-cells and CD58 located on APCs. Under various pathological conditions, which involve undesired immune response, inhibiting the CD2-CD58 interactions becomes a therapeutically relevant opportunity. Herein we present an extensive work to identify novel inhibiting agents of the CD2-CD58 interactions. Classical molecular dynamics (MD) simulations of the CD2-CD58 complex highlighted a series of crucial CD58 residues responsible for the interactions with CD2. Based on such results, a pharmacophore map, complementary to the CD2-binding site of CD58, was created and employed for virtual screening of ~ 300,000 available compounds. On the ~ 6000 compounds filtered from pharmacophore mapping, ADME screening leads to ~ 350 molecules. Molecular docking was then performed on these molecules, and fifteen compounds emerged with significant binding energy (< - 50 kcal/mol) for CD58. Finally, short MD simulations were performed in triplicate on each complex (i) to provide a microscopic view of the ligand binding and (ii) to rule out possibly weak binders of CD58 from the identified hits. At last, we suggest eight compounds for in vitro testing that were identified as promising hits to bind CD58 with a high binding affinit

Shedding Light on the Photoisomerization Pathway of Donor-Acceptor Stenhouse Adducts

Donor-acceptor Stenhouse adducts (DASAs) are negative photochromes that hold great promise for a variety of applications. Key to optimizing their switching properties is a detailed understanding of the photoswitching mechanism, which, as yet, is absent. Here we characterize the actinic step of DASA-photoswitching and its key intermediate, which was studied using a combination of ultrafast visible and IR pump-probe spectroscopies and TD-DFT calculations. Comparison of the time-resolved IR spectra with DFT computations allowed to unambiguously identify the structure of the intermediate, confirming that light absorption induces a sequential reaction path in which a Z-E photoisomerization of C-2-C-3 is followed by a rotation around C-3-C-4 and a subsequent thermal cyclization step. First and second-generation DASAs share a common photoisomerization mechanism in chlorinated solvents with notable differences in kinetics and lifetimes of the excited states. The photogenerated intermediate of the second-generation DASA was photo-accumulated at low temperature and probed with time-resolved spectroscopy, demonstrating the photoreversibility of the isomerization process. Taken together, these results provide a detailed picture of the DASA isomerization pathway on a molecular level

Formazanate boron difluoride dyes: discrepancies between TD-DFT and wavefunction descriptions

International audienceIn this work, we investigate the ground- and excited-state structures as well as the optical properties of a series of five formazanate dyes using state-of-the-art density-based and wavefunction-based methods. The present work is the first to evaluate the properties of formazanate-BF2 dyes with wavefunction-correlated schemes. Firstly, we show that CC2 provides more twisted ground-state geometries than DFT while both approaches lead to planar excited-state structures. Secondly, we demonstrate that the differences between the transition energies computed at TD-DFT, CIS(D), SOS-CIS(D), ADC(2), and CC2 levels are large and that the optical spectra also significantly depend on the selected geometries. Indeed, CC2 fluorescence energies computed on TD-DFT structures significantly differ from their full-CC2 counterparts. Thirdly, we discuss the importance of solvent effects evaluated with various continuum models. Fourthly, we provide comparisons with experiment. © 2016, Springer-Verlag Berlin Heidelberg

Computational simulations determining disulfonic stilbene derivative bioavailability within human serum albumin

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Influence of the Nature of the Amino Group in Highly Fluorescent Difluoroborates Exhibiting Intramolecular Charge Transfer

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Excited-State Intramolecular Proton Transfer Dyes with Dual-State Emission Properties: Concept, Examples and Applications

Dual-state emissive (DSE) fluorophores are organic dyes displaying fluorescence emission both in dilute and concentrated solution and in the solid-state, as amorphous, single crystal, polycrystalline samples or thin films. This comes in contrast to the vast majority of organic fluorescent dyes which typically show intense fluorescence in solution but are quenched in concentrated media and in the solid-state owing to &pi;-stacking interactions; a well-known phenomenon called aggregation-caused quenching (ACQ). On the contrary, molecular rotors with a significant number of free rotations have been engineered to show quenched emission in solution but strong fluorescence in the aggregated-state thanks to restriction of the intramolecular motions. This is the concept of aggregation-induced emission (AIE). DSE fluorophores have been far less explored despite the fact that they are at the crossroad of ACQ and AIE phenomena and allow targeting applications both in solution (bio-conjugation, sensing, imaging) and solid-state (organic electronics, data encryption, lasing, luminescent displays). Excited-State Intramolecular Proton Transfer (ESIPT) fluorescence is particularly suitable to engineer DSE dyes. Indeed, ESIPT fluorescence, which relies on a phototautomerism between normal and tautomeric species, is characterized by a strong emission in the solid-state along with a large Stokes&rsquo; shift, an enhanced photostability and a strong sensitivity to the close environment, a feature prone to be used in bio-sensing. A drawback that needs to be overcome is their weak emission intensity in solution, owing to detrimental molecular motions in the excited-state. Several strategies have been proposed in that regard. In the past few years, a growing number of examples of DSE-ESIPT dyes have indeed emerged in the literature, enriching the database of such attractive dyes. This review aims at a brief but concise overview on the exploitation of ESIPT luminescence for the optimization of DSE dyes properties. In that perspective, a synergistic approach between organic synthesis, fluorescence spectroscopy and ab initio calculations has proven to be an efficient tool for the construction and optimization of DSE-ESIPT fluorophores

Design of hybrid conjugates based on chemical similarity

Conducting polymer-amino acid hybrid materials have been prepared by conjugating poly(3,4-ethylenedioxythiophene) (PEDOT) and an amino acid bearing a 3,4-ethylenedioxythiophene (EDOT) ring as a side group. Two amino acids have been designed, synthesized and characterized. These compounds differ in the presence or not of a methylene group between the EDOT ring and the backbone (i.e.I and II, respectively). The electrochemical properties of PEDOT and their conjugates with I and II (PEDOT-I and PEDOT-II) have been determined using cyclic voltammetry and electrochemical impedance spectroscopy, and subsequently compared. Incorporation of end capping amino acids has been found to increase the hydrophilicity of PEDOT surface, which is consistent with the better behaviour of the conjugates as the cellular matrix. The electronic properties of both the amino acids and the conjugates have been investigated by UV-vis spectroscopy. Results indicate that elimination of the methylene group of I provokes a reduction of 0.13 eV in the π-π* lowest transition energy (Eg) of the conjugate. This decrease is explained by the larger structural flexibility due to the methylene group in I. Calculations of the electronic properties of the two hybrids at the molecular level using quantum mechanical methods suggest that the end capping amino acids essentially affect the electronic intermolecular effects. © The Royal Society of Chemistry 2013.Financial support from the MICINN and FEDER (MAT2012-34498) and Generalitat de Catalunya (research group 2009 SGR 925 and XRQTC) is gratefully acknowledged. Support for the research of C.A. was received through the prize “ICREA Academia” for excellence in research funded by the Generalitat de Catalunya. G.F. thanks the financial support through a FPIUPC grant. A.D.L thanks the CEISAM laboratory for the warm welcome and the Institut de Chimie for supporting her installation in Nantes. D.J. acknowledges the European Research Council (ERC) and the Région des Pays de la Loire for financial support in the framework of a Starting Grant (Marches – 278845) and a recrutement sur poste stratégique, respectively.Peer Reviewe

Design of hybrid conjugates based on chemical similarity

Conducting polymer-amino acid hybrid materials have been prepared by conjugating poly(3,4-ethylenedioxythiophene) (PEDOT) and an amino acid bearing a 3,4-ethylenedioxythiophene (EDOT) ring as a side group. Two amino acids have been designed, synthesized and characterized. These compounds differ in the presence or not of a methylene group between the EDOT ring and the backbone (i.e.I and II, respectively). The electrochemical properties of PEDOT and their conjugates with I and II (PEDOT-I and PEDOT-II) have been determined using cyclic voltammetry and electrochemical impedance spectroscopy, and subsequently compared. Incorporation of end capping amino acids has been found to increase the hydrophilicity of PEDOT surface, which is consistent with the better behaviour of the conjugates as the cellular matrix. The electronic properties of both the amino acids and the conjugates have been investigated by UV-vis spectroscopy. Results indicate that elimination of the methylene group of I provokes a reduction of 0.13 eV in the π-π* lowest transition energy (Eg) of the conjugate. This decrease is explained by the larger structural flexibility due to the methylene group in I. Calculations of the electronic properties of the two hybrids at the molecular level using quantum mechanical methods suggest that the end capping amino acids essentially affect the electronic intermolecular effects. © The Royal Society of Chemistry 2013.Financial support from the MICINN and FEDER (MAT2012-34498) and Generalitat de Catalunya (research group 2009 SGR 925 and XRQTC) is gratefully acknowledged. Support for the research of C.A. was received through the prize “ICREA Academia” for excellence in research funded by the Generalitat de Catalunya. G.F. thanks the financial support through a FPIUPC grant. A.D.L thanks the CEISAM laboratory for the warm welcome and the Institut de Chimie for supporting her installation in Nantes. D.J. acknowledges the European Research Council (ERC) and the Région des Pays de la Loire for financial support in the framework of a Starting Grant (Marches – 278845) and a recrutement sur poste stratégique, respectively.Peer Reviewe

Electroactive polymer-peptide conjugates for adhesive biointerfaces

Electroactive polymer-peptide conjugates have been synthesized by combining poly(3,4-ethylenedioxythiophene), a polythiophene derivative with outstanding properties, and an Arg-Gly-Asp (RGD)-based peptide in which Gly has been replaced by an exotic amino acid bearing a 3,4-ethylenedioxythiophene ring in the side chain. The incorporation of the peptide at the ends of preformed PEDOT chains has been corroborated by both FTIR and X-ray photoelectron spectroscopy. Although the morphology and topology are not influenced by the incorporation of the peptide at the ends of PEDOT chains, this process largely affects other surface properties. Thus, the wettability of the conjugates is considerably higher than that of PEDOT, independently of the synthetic strategy, whereas the surface roughness only increases when the conjugate is obtained using a competing strategy (i.e. growth of the polymer chains against termination by end capping). The electrochemical activity of the conjugates has been found to be higher than that of PEDOT, evidencing the success of the polymer-peptide links designed by chemical similarity. Density functional theory calculations have been used not only to ascertain the conformational preferences of the peptide but also to interpret the electronic transitions detected by UV-vis spectroscopy. Electroactive surfaces prepared using the conjugates displayed the higher bioactivities in terms of cell adhesion, with the relative viabilities being dependent on the roughness, wettability and electrochemical activity of the conjugate. In addition to the influence of the peptide fragment in the initial cell attachment and subsequent cell spreading and survival, the results indicate that PEDOT promotes the exchange of ions at the conjugate-cell interface.Authors are indebted to supports from MINECO and FEDER (MAT2012-34498, and CTQ2013-40855-R), Generalitat de Catalunya (XRQTC), CESCA and Gobierno de Aragón-FSE (research group E40). D.J. is indebted to the European Research Council (ERC) for support in the framework of the ERC StG grant Marches 278845.Peer Reviewe