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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: SYNTHESIS, MOLECULAR MODELING AND EXPERIMENTALACTIVITY OF SOME NEW ACETAMIDE, BENZAMIDE ANDPHENYLMETHANONE DERIVATIVES AS SIGMA LIGANDS.

Titolo: MoDeNa Nanotools: An integrated multiscale simulation workflow to predict thermophysical properties of thermoplastic polyurethanes
Abstract: In this work we describe and assess the performance of Nanotools, a feature of the MoDena software we arecurrently developing in the framework of a granted EU project devoted to the implementation of a multi-scale modeling environment for nanomaterials and systems by design. Specifically, Nanotools integratesmulti-step computational procedures based on atomistic molecular dynamics and Monte Carlo simula-tions for the estimation of major thermophysical properties of thermoplastic polyurethanes (TPUs). Thepredicted results obtained with Nanotools for density, thermal conductivity, surface tension, gas perme-ability, and Young modulus are in good agreement with the relevant experimental data, thus paving theway for the use of Nanotools in the current design of new TPUs for advanced applications.

Titolo: Computer-assisted design, synthesis, binding and cytotoxicity assessments of new 1-(4-(aryl(methyl)amino)butyl)-heterocyclic sigma 1 ligands
Abstract: In this work we applied a blend of computational and synthetic techniques with the aim to design, synthesize, and characterize new σ1 receptor (σ1R) ligands. Starting from the structure of previously reported, high-affinity benzoxazolone-based σ1 ligands, the threedimensional homology model of the σ1R was exploited for retrieving the
molecular determinants to fulfill the optimal pharmacophore requirements. Accordingly, the benzoxazolone moiety was replaced by other heterocyclic scaffolds, the relevant conformational space in the σ1R binding cavity was explored, and the effect on σ1R binding affinity was ultimately assessed. Next, the compounds designed in silico were synthesized, and their affinity and selectivity toward σ1 and σ2 receptors were tested. Finally, a representative series of best σ1R binders were assayed for cytotoxic activity on the SH-SY5Y human neuroblastoma cell line. Specifically, the new 4-phenyloxazolidin-2-one derivatives 2b (i.e., (R)-2b and (S)-2b) emerged as potential leads for further development as σ1R agents, as they were found endowed with the highest σ1R affinity (Kiσ1 values in the range 0.95-9.3 nM), and showed minimal cytotoxic levels exhibited in the selected, cell-based test, in line with a σ1R agonist behavior.

Titolo: Exploring new structures in the development of new sigma ligands
Abstract: To date, the research in the field of sigma receptors (sR) still remains difficult, considering the fact that
only the s1 subtype was purified and cloned from several animal species including man, while the s2R
subtype has not been cloned yet and still remains an unknown protein. Is well-known that s1R has been
associated with many diseases including stroke, cocaine addiction, pain, cancer, and neurodegenerative
pathologies1 while s2R subtype are overexpressed in several tumor cells. By these considerations the s1
ligands could be used as neuroprotective agents, while s2 ligands can be considered a tool for cancer
therapy and diagnosis (as PET or SPECT).
Starting from the structure of previously reported2, high-affinity benzoxazolone-based s1 ligands, the
three-dimensional homology model of the s1R was exploited for retrieving the molecular determinants to
fulfill the optimal pharmacophore requirements. Accordingly, the benzoxazolone moiety was replaced by
other heterocyclic scaffolds, the relevant conformational space in the s1R binding cavity was explored,
and the effect on s1R binding affinity was ultimately assessed. Next, the compounds designed in silico
were synthesized, and their affinity and selectivity toward s1 and s2 receptors were tested.
We designed and synthesized two new series of compounds 1a-h and 2a-h as potential sigma ligands. The highest s1 affinity (Ki= 16nM) was reached by compound 1a (R=H; R’= CH3); towards s2R the best
result was obtained by derivative 2h (R= 2,4(CH3)2; R’= cyclohexyl), with a Ki value of 80 nM.

Titolo: Benzoxazinones and correlated scaffolds linked to benzylamino moieties through a butylene spacer. New sigma receptor ligands

Titolo: Cationic carbosilane dendrimers and oligonucleotide binding: an energetic affair
Abstract: GENERATION 2 CATIONIC CARBOSILANE DENDRIMERS HOLD GREAT PROMISE AS INTERNALIZING AGENTS FOR GENE THERAPY AS THEY PRESENT LOW TOXICITY AND RETAIN AND INTERNALIZE GENETIC MATERIAL AS OLIGONUCLEOTIDE OR SIRNA. IN THIS WORK WE CARRIED OUT A COMPLETE IN SILICO STRUCTURAL AND ENERGETICAL CHARACTERIZATION OF THE INTERACTIONS OF A SET OF 2G CARBOSILANE DENDRIMERS, SHOWING DIFFERENT AFFINITY TOWARDS TWO SINGLE STRAND OLIGONUCLEOTIDE (ODN) SEQUENCES IN VITRO. OUR SIMULATIONS PREDICT THAT THESE FOUR DENDRIMERS AND THE RELEVANT ODN COMPLEXES ARE CHARACTERIZED BY SIMILAR SIZE AND SHAPE, AND THAT THE MOLECULE-SPECIFIC ODN BINDING ABILITY CAN BE RATIONALIZED ONLY CONSIDERING A CRITICAL MOLECULAR DESIGN PARAMETER: THE NORMALIZED EFFECTIVE BINDING ENERGY ΔGBIND,EFF/NEFF I.E., THE PERFORMANCE OF EACH ACTIVE INDIVIDUAL DENDRIMER BRANCH DIRECTLY INVOLVED IN A BINDING INTERACTION

Titolo: Nano tools for macro problems: multiscale molecular modeling of nanostructured polymer systems
Abstract: A current challenge of physical, chemical, and engineering sciences is to develop theoretical tools for predicting structure and properties of complex materials from the knowledge of a few input parameters. In this work, we present a general multiscale molecular simulation protocol for predicting morphologies and properties of nanostructured polymer systems and we apply it to three examples of industrial relevance. The first example is of general importance for the polymer industry and is related to the enhancement of mechanical and barrier properties, if a nanofiller is dispersed into a polymer matrix: the role of multiscale modeling for the development of the material in the stage of screening, the best design is evidenced. The second example, important for the optoelectronic industry, is related to the prediction of the dispersion of gold nanoparticles into a diblock copolymer system forming different nanostructures (lamellae, cylinders, …). In this case, it is relevant to understand how it is possible to influence the self-assembly of the nanoparticles in different regions of the diblock copolymer structure. The third example is of interest to automotive and polymer industries and involves inorganic nanoparticles grafted with organic side chains. The assembly is dispersed in a polymeric matrix and it is interesting to predict the effect of the chain length and grafting density on the nanostructure.

Titolo: Size and shape matter! A multiscale molecular simulation approach to polymer nanocomposites
Abstract: Multiscale molecular modeling (MsM) techniques are applied in many fields of material science, but it is particularly important in the polymer field, due to the wide range of phenomena occurring at different scales which influence the ultimate properties of the materials. In this context, MsM plays a crucial role in the design of new materials whose properties are influenced by the structure at nanoscale. In this work we present the application of a multiscale molecular modeling procedure to characterize a different set of polymer-based nanocomposites (PNCs) obtained with full/partial dispersion of different nanofillers in different polymeric matrices. This approach relies on a step-by step message-passing technique from atomistic to mesoscale to finite element level, and the calculated results are compared to available experimental evidences. In details, 13 PNC systems have been studied by different molecular modeling methods, such as atomistic Molecular Mechanics and Molecular Dynamics, mesoscale Dissipative Particles Dynamics, and macroscale Finite Element Method, and their mechanical, thermal and barrier properties have been predicted in agreement with the available experimental data.

Titolo: Development of a methodology for the sustainability evaluation of industrial pharmaceutical processes
Abstract: This work extends a general framework for the prediction of industrial sustainability, i.e. Process Sustainability Prediction (PSP) Framework proposed by Fermeglia et al. [1], by implementing features for treating the sustainability estimation of batch pharmaceutical processes. The resulting procedure allows performing evaluation of different industrial batch plants alternatives using representative indicators and metrics that cover the three aspects of sustainability: economy, environment and society. Two kinds of sustainability indicators are adopted: three dimensional indicators (3D-indicators) and one dimensional indicators (1D-indicators). The methodology proposed by Martins et al. [2], containing 3D-indicators, has been updated, modified and extended including the concept of time, related to discontinuous processes as pharmaceutical ones. The methodology takes into account E-factor (proposed by Sheldon [3]), energy intensity, potential chemical risk and potential environmental impact modified by considering the cycle time of batch reactors. The 3D-indicators are calculated using the results obtained from process simulation coupled with the toxicological database, containing data from EPA, other sources, and an in-house procedure for the estimation of toxicological properties based on molecular modelling.
Whenever a more sophisticated evaluation of the impact is needed, one may resort to the evaluation of 1D-indicators. One dimensional indicators are focused on single contribution to sustainability, e.g. Waste Reduction Algorithm (WAR) [4] focused on environmental issues, Profit Intensity, an index based on Materials Intensity [2] and modified to inspect economic aspects, and HTP (Hazard Toxicity Potential) developed to define the hazard risk for employers inside the chemical plant.
In this paper, we have modified the original framework of WAR by including the time of charge, reaction and discharge from reactor and the introduction of new chemicals for rinsing for taking into account more closely the industrial operation in this sector. Some other changes have been done on environmental impact categories to obtain more reliable data on environmental issues only. Process data are extracted from process simulation software, coupled with toxicological data and with a molecular modelling procedure based on quantum chemistry (COSMO-RS) for the prediction of toxicological properties.