R.E.D. Server: a web service for deriving RESP and ESP charges and building force field libraries for new molecules and molecular fragments

R.E.D. Server is a unique, open web service, designed to derive non-polarizable RESP and ESP charges and to build force field libraries for new molecules/molecular fragments. It provides to computational biologists the means to derive rigorously molecular electrostatic potential-based charges embedded in force field libraries that are ready to be used in force field development, charge validation and molecular dynamics simulations. R.E.D. Server interfaces quantum mechanics programs, the RESP program and the latest version of the R.E.D. tools. A two step approach has been developed. The first one consists of preparing P2N file(s) to rigorously define key elements such as atom names, topology and chemical equivalencing needed when building a force field library. Then, P2N files are used to derive RESP or ESP charges embedded in force field libraries in the Tripos mol2 format. In complex cases an entire set of force field libraries or force field topology database is generated. Other features developed in R.E.D. Server include help services, a demonstration, tutorials, frequently asked questions, Jmol-based tools useful to construct PDB input files and parse R.E.D. Server outputs as well as a graphical queuing system allowing any user to check the status of R.E.D. Server jobs

Synthèse et étude biologique de dérivés benzo[c]phénanthridiniques à visée antitumorale (Essais de couplage à de nouveaux marqueurs fluorescents semi-conducteurs nanocristallins)

Les benzo[c]phénanthridines (BZPs) sont des alcaloïdes poly-aromatiques possédants une activité antitumorale sur les lignées leucémiques murines L1210 et P388. La synthèse de la fagaronine (molécule naturelle) a été entreprise et une pharmacomodulation a été effectuée sur le squelette carboné pour aboutir à des dérivés dont l'éthoxidine. Une étude biologique approfondie a été réalisée sur l'éthoxidine. Différents métabolites ont été isolés, et nous avons noté la présence de la 12-éthoxyfagaronine possédant une structure hybride de l'éthoxidine et de la fagaronine. La synthèse de ces différents métabolites a été entreprise. Afin de faciliter la mise en oeuvre de tests biologiques, le marquage de telles molécules peut être intéressant. Nous avons donc caractérisé et hydrosolubilisé de nouveaux marqueurs fluorescents semi-conducteurs nanocristallins (quantum dots). Différents essais de bioconjugaison de quantum dots ont été entrepris sur une BZP modifiée dérivée de la 12-éthoxyfagaronine.Benzo[c]phenanthridines are polyaromatic alkaloids having an antitumor activity against mice leukemia L1210 and P388. Synthesis of fagaronine (natural extract) have been undertaken and a pharmacomodulation has given ethoxidine. A detailed biologic studies has been realized and different metabolites have been isolated and more particularly the 12-ethoxyfagaronine who have a mixed structure between ethoxidine and fagaronine. Synthesis of those different metabolites have been undertaken. In order to understand biologic activity, fluorescent marking of organic molecules could be useful. We have then characterized and hydrosolubilized new fluorescent semi-conductors nanocrystallites (quantum dots). Different trial of bioconjugaison of quantum dots to modified BZP derived from 12-ethoxyfagaronine have been attempted.ANGERS-BU Médecine-Pharmacie (490072105) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Crystal Structure of Ethoxidine, A Synthetic Quaternary Benzo[c]phenanthridine

International audienceThe complete structure of N-methyl-12-ethoxy-2,3,8,9-tetramethoxybenzo[c]phenanthridinium methylsulfonate salt 1, also named ethoxidine, was established by a single-crystal X-ray analysis. The crystal is triclinic, space group P1− with a = 14.1836 (11), b = 14.2803 (11), c = 14.3073 (12) Å, β = 77.699 (5)°, V = 2422.3 (3) Å3, Z = 4, 2 C25H29NO8S, D c = 1.381 g/cm3, μ (CuKα) = 1.5418 Å, S = 1.036, F (000) = 1064.00, R = 0.0594 and wR = 0.1446. In the unit cell, there are two independent molecules. Solid-state data could be used to enlighten the biological mechanism of action.</p

Multi-Mannosides Based on a Carbohydrate Scaffold: Synthesis, Force Field Development, Molecular Dynamics Studies, and Binding Affinities for Lectin Con A

14 páginas, 3 figuras, 1 tabla, 3 esquemas.A short and efficient strategy for the synthesis of multi-valent mannosides based on a selectively functionalized carbohydrate scaffold was reported involving (i) direct regioselective azidation of unprotected commercial saccharides, (ii) acetylation, (iii) grafting of the mannosyl ligands by click chemistry, and (iv) deacetylation. New glycoclusters with a valency ranging from 1 to 4 and different spatial arrangements of the epitopes were obtained. Binding affinities of the new glycoclusters toward concanavalin A (Con A) lectin were investigated by an enzyme-linked lectin essay (ELLA). The synthetic multi-valent compounds exhibited a remarkable cluster effect with a relative potency per mannoside residue ranging from 8.1 to 9.1 depending on the structures. ELLA experiments were in agreement with the establishment of favorable interactions between triazole ring and Con A, increasing the binding affinity. A new force field topology database was developed in agreement with the GLYCAM 2004 force field. Molecular dynamics performed on representative glyco-conjugates revealed interesting structural features such as rigidity of the scaffold for a well-defined presentation of the ligands and highly flexible mannose counterparts. The new glycoconjugates reported may be promising tools as probes or effectors of biological processes involving lectins.This work was carried out with financial support from the Centre National de la Recherche Scientifique and the Ministère Délégué à l'Enseignement Supérieur et à la Recherche.Peer reviewe

Multi-Mannosides Based on a Carbohydrate Scaffold: Synthesis, Force Field Development, Molecular Dynamics Studies, and Binding Affinities for Lectin Con A

14 páginas, 3 figuras, 1 tabla, 3 esquemas.A short and efficient strategy for the synthesis of multi-valent mannosides based on a selectively functionalized carbohydrate scaffold was reported involving (i) direct regioselective azidation of unprotected commercial saccharides, (ii) acetylation, (iii) grafting of the mannosyl ligands by click chemistry, and (iv) deacetylation. New glycoclusters with a valency ranging from 1 to 4 and different spatial arrangements of the epitopes were obtained. Binding affinities of the new glycoclusters toward concanavalin A (Con A) lectin were investigated by an enzyme-linked lectin essay (ELLA). The synthetic multi-valent compounds exhibited a remarkable cluster effect with a relative potency per mannoside residue ranging from 8.1 to 9.1 depending on the structures. ELLA experiments were in agreement with the establishment of favorable interactions between triazole ring and Con A, increasing the binding affinity. A new force field topology database was developed in agreement with the GLYCAM 2004 force field. Molecular dynamics performed on representative glyco-conjugates revealed interesting structural features such as rigidity of the scaffold for a well-defined presentation of the ligands and highly flexible mannose counterparts. The new glycoconjugates reported may be promising tools as probes or effectors of biological processes involving lectins.This work was carried out with financial support from the Centre National de la Recherche Scientifique and the Ministère Délégué à l'Enseignement Supérieur et à la Recherche.Peer reviewe

Multimeric Lactoside “Click Clusters” as Tools to Investigate the Effect of Linker Length in Specific Interactions with Peanut Lectin, Galectin-1, and -3

13 páginas, 8 figuras, 1 tabla, 3 esquemasMultimeric lactosides based on carbohydrate scaffolds with valencies ranging from 1 to 4 and different linker lengths were synthesized by a copper-catalyzed azide–alkyne cycloaddition (CuAAC). The binding affinities and crosslinking abilities of the new “click clusters” toward biologically relevant galectins (gal-1, gal-3) and peanut lectin were evaluated by fluorescent polarization assay (FPA) and enzyme-linked lectin assay (ELLA), respectively. FPA indicated that the binding affinities of the synthetic multilactosides towards the galectins increased proportionally with their lactosyl content, without significant differences due to the spacer length. ELLA evidenced a modest cluster effect for the multivalent conjugates, with a relative potency per lactoside ranging from 2.1 to 3.2. Nearly identical binding affinities were recorded for derivatives differing in the length of the linkers, in agreement with the FPA data. These results demonstrate that this parameter does not significantly influence the recognition process when interactions occur at a single lectin site. Molecular dynamics revealed that glycoconjugates adopt a pseudoglobular structure with a random localization of the lactoside residues. These spatial distributions were observed irrespective of the linker length; this explains the virtually equal affinities recorded by ELLA. In contrast, two-site “sandwich” ELLA clearly revealed that multivalent derivatives bearing the longest spacers were more efficient for crosslinking lectins. Intrinsic affinities, devoid of aggregation effects, and crosslinking capabilities are, therefore, not directly related phenomena that must be taking into consideration in neoglycoconjugate design for specific applications.This work was carried out with financial support from the Centre National de la Recherche Scientifique, the Ministère Délégué à l'Enseignement Supérieur et à la Recherche and the Conseil Régional de Picardie.Peer reviewe

Synthesis, Physicochemical Studies, Molecular Dynamics Simulations, and Metal-Ion-Dependent Antiproliferative and Antiangiogenic Properties of Cone ICL670-Substituted Calix[4]arenes.

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