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Titolo: Nanozapped! DNA and its dendritic nanovectors: a combined in silico/in vitro approach

Titolo: Approccio di ingegneria molecolare per lo studio della farmaco-resistenza nella terapia oncologica

Titolo: Development of a methodology for the sustainability evaluation of industrial pharmaceutical processes
Abstract: -

Titolo: Tra analogico e digitale. Ricordando Franco Fileni
Abstract: studi in memoria di Franco Fileni

Titolo: Hitting the right spot: Mechanism of action of OPB-31121, a novel and potent inhibitor of the Signal Transducer and Activator of Transcription 3 (STAT3)
Abstract: STAT3 is a key element inmany oncogenic pathways and, like other transcriptionfactors, is an attractive target for development of novel anticancer drugs. However, interfering with STAT3 functions has been a difficult task and very fewsmallmolecule inhibitors havemade theirway to the clinic. OPB-31121, an anticancer compound currently in clinical trials, has been reported to affect STAT3 signaling, although its mechanism of action has not been unequivocally demonstrated. In this study, we used a combined computational and experimental approach to investigate the molecular target and the mode of interaction of OPB-31121 with STAT3. In parallel, similar studies were performed with known STAT3 inhibitors (STAT3i) to validate our approach. Computational docking and molecular dynamics simulation (MDS) showed that OPB-31121 interacted with high affinity with the SH2 domain of STAT3. Interestingly, there was no overlap of the OPB-31121 binding site with those of the other STAT3i. Computational predictions were confirmed by in vitro binding assays and competition experiments alongwith site-directedmutagenesis of critical residues in the STAT3 SH2 domain. Isothermal titration calorimetry experiments demonstrated the remarkably high affinity ofOPB-31121 for STAT3 with Kd (10 nM) 2e3 orders lower than other STAT3i. Notably, a similar ranking of the potency of the compoundswas observed in terms of inhibition of STAT3phosphorylation, cancer cell proliferation and clonogenicity. These results suggest that the highaffinity and efficacy of OPB-31121 might be related to the unique features and mode of interaction of OPB-31121 with STAT3. These unique characteristics make OPB-31121 a promising candidate for further development and an interesting lead for designing new,more effective STAT3i.

Titolo: Life Cycle Analysis applied to acrylic acid production process with different fuels for steam generation
Abstract: Acrylic acid, one of the most important monomers, has a wide range of uses e.g. in the paints adhesives, textile finishing, leather processing or super absorbents. The production process from propylene is well known and used at industrial scale in the USA, Europe, and Asia. The present paper focuses on the evaluation of the environmental impact of the acrylic acid production process from propylene. Steam is a major raw material in the process under study, consequently different paths to obtain steam are investigated. The process was simulated using commercial software (Aspen Plus, PROII). A productivity capacity of 50,000 tones/year of acrylic acid has been considered. The environmental assessment, evaluated using Life Cycle Analysis method, depends on the material and energy balances generated by simulations.
The present work uses a cradle-to-grave approach. The functional unit, to which all the environmental results for the cases under study are reported, is one tone of acrylic acid produced. The boundaries of the system cover: i) acrylic acid production; ii) upstream processes for example catalyst and molten salt production; steam production using various fuels (e.g. natural gas, anthracite, lignite, heavy fuel oil, light fuel oil and biomass) and iii) downstream processes for example: acrylic acid and acetic acid transport to other chemical plants for further processing. The CML (An LCA method developed by the Center of Environmental Science of Leiden University) 2001 impact assessment method was used for comparison between different case studies. The best value for Global Warming Potential (GWP) e.g. 1094.5 kg CO2-Equiv./tone is obtained when biomass is used to generate the steam required by the process. For other indicators such as Acidification Potential (AP), Photochemical Oxidation Potential (PCOP) and Eutrophication Potential (EP), the best value is obtained when steam is generated from natural gas. A sensitivity analysis of the environmental impact categories using the different combination of natural gas and biomass was also investigated. The study investigates also the association of the post-combustion aminebased
carbon capture technologies with the conventional acrylic acid production process. Such association decreases the value of some environmental impact categories (e.g. GWP) while other impact categories are increasing e.g. AP, Human Toxicity Potential (HTP), Terrestrial Ecotoxicity Potential (TETP).

Titolo: Mastering dendrimer self-assembly for efficient siRNA delivery: from conceptual design to in vivo efficient gene silencing
Abstract: Self-assembly is a fundamental concept and a powerful approach in molecular science. However, creating functional materials with the desired properties through self-assembly remains challenging. In this work, through a combination of experimental and computational approaches, we report on the self-assembly of small amphiphilic dendrons into nanosized supramolecular dendrimer micelles with a degree of structural definition similar to traditional covalent high-generation dendrimers. We demonstrate that, with the optimal balance of hydrophobicity and hydrophilicity, one of the self-assembled nanomicellar systems, totally devoid of toxic side effects, is able to deliver small interfering RNA (siRNA) and achieve effective gene silencing both in cells - including the highly refractory human hematopoietic CD34+ stem cells - and in vivo, thus paving the way for future biomedical implementation. This work presents a case study of the concept of generating functional supramolecular dendrimers via self-assembly. The ability of carefully designed and gauged building blocks to assemble into supramolecular structures opens new perspectives on the design of self-assembling nanosystems for complex and functional applications.

Titolo: Homology Model and Docking-Based Virtual Screening for Ligands of the σ1 Receptor
Abstract: This study presents for the first time the 3D model of the σ1 receptor protein as
obtained from homology modeling techniques, shows the applicability of this structure to
docking-based virtual screening, defines a computational strategy to optimize the results based on
a combination of 3D pharmacophore-based docking and MM/PBSA free energy of binding
scoring, and provides evidence that these in silico models and recipes are powerful tools on which
virtual screening of new σ1 ligands can be based. In particular, the validation of the applicability of
docking-based virtual screening to homology models is of utmost importance, since no crystal
structure is available to date for the σ1 receptor, and this missing information still constitutes a
major hurdle for a rational ligand design for this important protein target.

Titolo: Rigidity versus flexibility: is this an issue in S1 (sigma-1) receptor ligand affinity and activity?
Abstract: A set of stereoisomeric 2,5-diazabicyclo[2.2.2]octanes 14 and 15 was prepared in a chiral-pool synthesis starting from (S)- or (R)-aspartate. The key step in the synthesis was a Dieckmann-analogous cyclization of (dioxopiperazinyl)acetates 8, which involved trapping uf the intermediate hemiketal anion with Me3SiCl. The σ1 affinity was tested using membrane preparations from animal (guinea pig) and human origin. The binding of bicyclic compounds was analyzed by molecular dynamics simulations based on a 3D homology model of the σ1 receptor. The good correlation between Ki values observed in the σ1 assays and calculated free binding energy, coupled with the identification of four crucial ligand/receptor interactions allowed the formulation of structure affinity relationships. In an in vitro antitumor assay with seven human tumor cell lines, the bicyclic compounds inhibited selectively the growth of the cell line A427, which is due to induction of apoptosis. In this assay, the compounds behave like the known σ1 receptor antagonist haloperidol.

Titolo: Dal computer alla cellula: evidenze sperimentali/computazionali per il design di nanovettori efficienti per terapia genica.