Abstract: Estrogen replacement therapy is one of the most efficient treatment of menopausal symptoms. Unfortunately, despite the benefits of estrogenic therapy evidence exists of increasing number of cases of reproductive tissue cancer. This lead to a strong interest in discovering new compounds that display the benefits of estrogens avoiding such risks. We decided to apply a virtual high throughput screening, based on docking simulations, for the identification of new possible selective receptor compounds.

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Abstract: Estrogen Receptor belongs to the Nuclear receptor family, there are two different currently known subtypes Era and Erb. Levels and proportion of the two subtypes differs in different target cells. We can hypotheses a different pharmacological activity upon ligand binding. The aim of this work is the investigation through molecular dynamics simulations, on both the subtypes a and b of the estrogen receptor, of possible differences among them and for the study of their dynamical behaviour.

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Abstract: Molecular docking is an efficient computational tool to predict the structures of protein-ligand complex. This kind of simulation is of fundamental importance for interpretation of numerous biochemical phenomena, providing useful information on the preferred binding sites of ligands, and therefore in rational drug design. Bovine β-lactoglobulin (BLG) is a small extracellular protein belonging to the lipocalin superfamily. Lipocalins have been classified as transport proteins with the remarkable ability of binding small hydrophobic molecules within the central cavity also known as calyx. Because of its stability, abundance and easiness of preparation BLG, has been frequently studied to clarify its structural and binding features. Several studies suggest that more than one binding site exists, thus the aim of this work is to investigate the existence of other sites, in addition to the calyx one, and to verify if BLG can interact and play the role of carrier of drugs. We considered the particular case of Norfloxacin which is a broad-spectrum antibiotic used in treatment of urinary tract infections.

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Abstract: Gas1p is an exocellular glycoprotein of Saccharomyces cerevisiae and plays a crucial role in cell wall assembly, due to its β-(1,3)-glucan transferase activity. The identification of Gas1p homologues in other yeast species and fungi allowed the definition of a new family of glycosyl hydrolases, family GH72, on the basis of sequence similarity. Hydrophobic cluster analysis of the catalytic domain (C-domain) of some GH72 members suggests a (β/α)8 barrel fold, also supported by our recent study on the structural and functional characteristics of the C-domain of Gas1p. Standard homology modelling approaches cannot be used to infer the structure of C-domain of Gas1p and related proteins, due to the lackness of suitable homologues of known 3D structures. Threading and fold recognition approaches have been shown to predict fold of novel proteins with relatively high accuracy. However it should be noted that the detection of possible remote homologues is only the first step of successful modelling. In fact alignment to the same scaffold produced by different threading methods can be significantly dissimilar and affected by local errors, making difficult the derivation of a good structural model. With the aim of unraveling the key molecular characteristics of the C-domain of Gas1p and related proteins, in the present work, a procedure has been worked in which data derived from threading methods, multiple sequence alignments and secondary structure predictions were merged and compared to experimental results in order to obtain reliable and detailed three dimensional models.

Abstract: Ras proteins are guanine nucleotide binding enzymes, with intrinsic low GTP-ase activity, involved in the control of cell growth and cell differentiation. They act as molecular switches, cycling between active GTPbound state and inactive GDP-bound state. Ras activation state is regulated by the competing activity of GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs), the latter promoting the activation of Ras catalysing the exchange of GDP with GTP. In most tumors the activity of Ras proteins is altered, resulting in hyperactive GTP-bound forms of Ras, either because of a reduced GTPase activity or because of an increased GDP/GTP exchange. GEF mutant W809E/T935E (GEFmut) results in a dominant negative GEF, catalitically inactive, which binds to Ras with great affinity and forms a stable complex in the presence of excess nucleotide. By means of Molecular Dynamics (MD) simulations we compared different trajectories of Ras-GEFwt and Ras-GEFmut systems and analyzed them in terms of both energetic and structural parameters, to correlate the conformational differences of wt and mutant GEFs during their interaction with Ras with the observed modifications in Ras biological activity.