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Titolo: Class-based cape open interface revisited in net framework

Titolo: Mallard blue: a high-affinity selective heparin sensor that operates in highly competitive media
Abstract: We report the simple synthesis and full investigation of a novel heparin binding dye, mallard blue, an arginine-functionalized thionine. This dye binds heparin in highly competitive media, including water with high levels of competitive electrolyte, buffered aqueous solution and human serum. The dye reports on heparin levels by a significant change in its UV-vis spectroscopic profile. Molecular dynamics modeling provides detailed insight into the binding mode. Heparin binding is shown to be selective over other glycosaminoglycans, such as hyaluronic acid and chondroitin sulfate. Importantly, we demonstrate that, in the most competitive conditions, mallard blue outperforms standard dyes used for heparin sensing such as azure A.

Titolo: Structurally Flexible Triethanolamine Core PAMAM Dendrimers Are Effective Nanovectors for DNA Transfection in Vitro and in Vivo to the Mouse Thymus
Abstract: With the aim of developing dendrimer nanovectors with a precisely controlled architecture and flexible structure for DNA transfection, we designed PAMAM
dendrimers bearing a triethanolamine (TEA) core, with branching units pointing away from the center to create void spaces, reduce steric congestion, and increase water accessibility for the benefit of DNA delivery. These dendrimers are shown to form stable nanoparticles with DNA, promote cell uptake mainly via macropinocytosis, and act as effective nanovectors for DNA transfection in vitro on epithelial and fibroblast cells and, most importantly, in vivo in the mouse thymus, an exceedingly challenging organ for immune gene therapy. Collectively, these results validate our rational design approach of structurally flexible dendrimers with a chemically defined structure as effective nanovectors for gene delivery, and demonstrate the potential of these dendrimers in intrathymus gene delivery for future applications in immune gene therapy.

Titolo: Another Brick in the Wall. Validation of the σ1Receptor 3D Model by Computer-Assisted Design, Synthesis, and Activity of New σ1Ligands
Abstract: Originally considered an enigmatic polypeptide, the σ1 receptor has recently been identified as a unique ligand- regulated protein. Many studies have shown the potential of σ1 receptor ligands for the treatment of various diseases of the central nervous system (CNS); nevertheless, almost no information about the 3D structure of the receptor and/or the possible modes of interaction of the σ1 protein with its ligands have been unveiled so far. With the present work we validated our σ1 3D homology model and assessed its reliability as a platform for σ1 ligand structure-based drug design. To this purpose, the 3D σ1 model was exploited in the design of 33 new σ1 ligands and in their ranking for receptor affinity by extensive molecular dynamics simulation-based free energy calculations. Also, the main interactions involved in receptor/ligand binding were analyzed by applying a per residue free energy deconvolution and in silico alanine scanning mutagenesis calculations. Subsequently, all compounds were synthesized in our laboratory and tested for σ1 binding activity in vitro. The agreement between in silico and in vitro results confirms the reliability of the proposed σ1 3D model in the a priori prediction of the affinity of new σ1 ligands. Moreover, it also supports and corroborates the currently available biochemical data concerning the σ1 protein residues considered essential for σ1 ligand binding and activity.

Titolo: 3-Aryl-2-[1H-benzotriazol-1-yl]acrylonitriles: A novel class of potent tubulin inhibitors

Titolo: Design, synthesis and antitubercular activity of 4-alkoxy-triazoloquinolones able to inhibit the M. tuberculosis DNA gyrase
Abstract: A number of new F-triazolequinolones (FTQs) and alkoxy-triazolequinolones (ATQs) were designed, synthesized and evaluated for their activity against Mycobacterium tuberculosis H37Rv. Five out of 21 compounds exhibited interesting minimum inhibitory concentration (MIC) values (6.6-57.9 microM), ATQs generally being more potent than FTQs. Two ATQs, 21a and 30a, were endowed with the best anti-Mtb potency (MIC = 6.9 and 6.6 microM, respectively), and were not cytotoxic in a Vero cell line. Tested for activity against M. tuberculosis DNA gyrase in a DNA supercoiling activity assay, 21a and 30a showed IC50 values (27-28 microM) comparable to that of ciprofloxacin (10.6 microM). 21a was next selected for screening against several Mtb strains obtained from clinical isolates, including multi-drug-resistant (MDR) variants.
Importantly, this compound was effective in all cases, with very promising MIC values (4 microM) in the case of some isoniazid/rifampicin-resistant Mtb strains. Finally, computer-based simulations revealed that the binding mode of 21a in the Mtb gyrase cleavage core complexed with DNA and the relevant network of intermolecular interactions are utterly similar to those described for ciprofloxacin, yielding a molecular rationale for the comparable anti-mycobacterial and DNA gyrase inhibition activity of this quinolone.

Titolo: Triazolopyridinyl-acrylonitrile derivatives as antimicrotubule agents: Synthesis, in vitro and in silico characterization of antiproliferative activity, inhibition of tubulin polymerization and binding thermodynamics
Abstract: In this paper we report the synthesis, in vitro anticancer activity, and the experimental/computational characterization of mechanism of action of a new series of E isomers of
triazolo[4,5-b/c]pyridin-acrylonitrile derivatives (6c-g, 7d-e, 8d-e, 9c-f, 10d-e, 11d-e). All new compounds are endowed with moderate to interesting antiproliferative activity against 9 different cancer cell lines derived from solid and hematological human tumors. Fluorescence-based assays prove that these molecules interfere with tubulin polymerization. Furthermore, isothermal titration calorimetry (ITC) provides full tubulin/compound binding thermodynamics, thereby ultimately qualifying and quantifying the interactions of these molecular series with the target protein. Lastly, the analysis based on the tight coupling of in vitro and in silico modelling of the interactions
between tubulin and the title compounds allows to propose a molecular rationale for their biological activity.

Titolo: β-catenin in Desmoid-Type Fibromatosis: deep insights on the role of T41A and S45F mutations on protein structure and gene expression
Abstract: Desmoid- type fibromatosis (DF) is a rare mesenchymal lesion with high risk of local recurrence. Specific β-catenin mutations (S45F) appeared to be related to this higher risk compared to T41A mutated or wild type (WT). We explored the influence of both mutations and WT on structure stability and affinity of β-catenin for α-catenin and the pattern of gene expression that may influence DF behavior. Using 33 surgically resected primary DFs harboring T41A (n=14), S45F (n=10) or WT (n=9), we performed a comparative molecular analysis by protein/protein interaction modeling, gene expression by DASL microarrays, human inflammation gene panel and assessment of immune system-based biomarkers by immunohistochemistry. Mutated proteins were more stable than WT and formed a weaker complex with α-catenin. Consensus unsupervised gene clustering revealed the presence of two DF group- mutated (T41A+S45F) and WT (p= 0.0047). The gene sets "Inflammatory- Defense- Humoral-Immune Response" and "Antigen Binding" were significantly enriched in T41A. The deregulation of 16 inflammation-related genes was confirmed. Low numbers of T- cells and TAM infiltrating the tumors and low/absent PD-1/PD-L1 expression were also identified. We demonstrated that mutated DFs (T41A or S45F) and WT are two distinct molecular subgroups with regard to β-catenin stability, α-catenin affinity and gene expression profiling. A different inflammation signature characterized the two mutated groups, suggesting a mediation either by T41A or S45F. Finally, all mutated cases showed a low number of TIL and TAM cells and a low or absent expression of PD-1 and PD-L1 consistent with β-catenin activation insensitive to check-point blockade.

Titolo: The long and winding road.Multiscale molecular modeling approach to the self-assembly of di/triblock copolymers for drug delivery in aqueous solution

Titolo: Multiscale molecular modelling for the design of nanostructures in materials and life sciences