Giuseppe Floresta

Development of a Sigma-2 Receptor affinity filter through a Monte Carlo based QSAR analysis

Abstract For the first time in sigma‐2 (&sgr;2) receptor field, a quantitative structure–activity relationship (QSAR) model has been built using pKi values of the whole set of known selective &sgr;2 receptor ligands (548 compounds), taken from the Sigma‐2 Receptor Selective Ligands Database (S2RSLDB) (http://www.researchdsf.unict.it/S2RSLDB/), through the Monte Carlo technique and employing the software CORAL. The model has been developed by using a large and structurally diverse set of compounds, allowing for a prediction of different populations of chemical compounds endpoint (&sgr;2 receptor pKi). The statistical quality reached, suggested that model for pKi determination is robust and possesses a satisfactory predictive potential. The statistical quality is high for both visible and invisible sets. The screening of the FDA approved drugs, external to our dataset, suggested that sixteen compounds might be repositioned as &sgr;2 receptor ligands (predicted pKi ≥ 8). A literature check showed that six of these compounds have already been tested for affinity at &sgr;2 receptor and, of these, two (Flunarizine and Terbinafine) have shown an experimental &sgr;2 receptor pKi > 7. This suggests that this QSAR model may be used as focusing screening filter in order to prospectively find or repurpose new drugs with high affinity for the &sgr;2 receptor, and overall allowing for an enhanced hit rate respect to a random screening. Graphical abstract Figure. No Caption available.

The Search for Potent, Small-Molecule HDACIs in Cancer Treatment: A Decade After Vorinostat

Histone deacetylases (HDACs) play a crucial role in the remodeling of chromatin, and are involved in the epigenetic regulation of gene expression. In the last decade, inhibition of HDACs came out as a target for specific epigenetic changes associated with cancer and other diseases. Until now, more than 20 HDAC inhibitors (HDACIs) have entered clinical studies, and some of them (e.g., vorinostat, romidepsin) have been approved for the treatment of cutaneous T‐cell lymphoma. This review provides an overview of current knowledge, progress, and molecular mechanisms of HDACIs, covering a period from 2011 until 2015.

Sigma-2 receptor ligands QSAR model dataset

The data have been obtained from the Sigma-2 Receptor Selective Ligands Database (S2RSLDB) and refined according to the QSAR requirements. These data provide information about a set of 548 Sigma-2 (σ2) receptor ligands selective over Sigma-1 (σ1) receptor. The development of the QSAR model has been undertaken with the use of CORAL software using SMILES, molecular graphs and hybrid descriptors (SMILES and graph together). Data here reported include the regression for σ2 receptor pKi QSAR models. The QSAR model was also employed to predict the σ2 receptor pKi values of the FDA approved drugs that are herewith included.

γ-Cyclodextrin as a Catalyst for the Synthesis of 2-Methyl-3,5-diarylisoxazolidines in Water

A green and efficient 1,3-dipolar cycloaddition of nitrones with different styrenes and cinnamates using a catalytic amount of γ-cyclodextrin (γ-CD) in water has been developed to give substituted isoxazolidines. γ-CD was found to be highly efficacious in carrying out this reaction under an eco-friendly environment, affording moderate to excellent yields and, in some cases, excellent diastereomeric excess (up to >95%) at 100 °C in 8-12 h. The catalyst can be easily recuperated and recycled for several times without loss of activity. Water, an eco-friendly reaction medium, has been utilized for the first time, to the best of our knowledge, in this reaction. The credit of the presented protocol includes high yields and catalyst reusability, and precludes the use of organic solvents. The use of in silico calculations allowed us to rationalize the obtained results and to improve the stereoselectivity.

Adipocyte fatty acid binding protein 4 (FABP4) inhibitors. A comprehensive systematic review

Small molecule inhibitors of adipocyte fatty acid binding protein 4 (FABP4) have attracted interest following the recent publications of beneficial pharmacological effects of these compounds. FABP4 is predominantly expressed in macrophages and adipose tissue where it regulates fatty acids (FAs) storage and lipolysis and is an important mediator of inflammation. In the past years, hundreds FABP4 inhibitors have been synthesized for effective atherosclerosis and diabetes treatments, including derivatives of niacin, quinoxaline, aryl-quinoline, bicyclic pyridine, urea, aromatic compounds and other novel heterocyclic compounds. This review provides an overview of the synthesized and discovered molecules as adipocyte fatty acid binding protein 4 inhibitors (FABP4is) since the synthesis of the putative FABP4i, BMS309403, highlighting the interactions of the different classes of inhibitors with the targets.

Hyphenated 3D-QSAR statistical model-scaffold hopping analysis for the identification of potentially potent and selective sigma-2 receptor ligands

A 3D quantitative structure-activity relationship (3D-QSAR) model for predicting the σ2 receptor affinity has been constructed with the aim of providing a useful tool for the identification, design, and optimization of novel σ2 receptor ligands. The model has been built using a set of 500 selective σ2 receptor ligands recovered from the sigma-2 receptor selective ligand database (S2RSLDB) and developed with the software Forge. The present model showed high statistical quality as confirmed by its robust predictive potential and satisfactory descriptive capability. The drawn up 3D map allows for a prompt visual comprehension of the electrostatic, hydrophobic, and shaping features underlying σ2 receptor ligands interaction. A theoretic approach for the generation of new lead compounds with optimized σ2 receptor affinity has been performed by means of scaffold hopping analysis. Obtained results further confirmed the validity of our model being some of the identified moieties have already been successfully employed in the development of potent σ2 receptor ligands. For the first time is herein reported a 3D-QSAR model which includes a number of chemically diverse σ2 receptor ligands and well accounts for the individual ligands affinities. These features will ensure prospectively advantageous applications to speed up the identification of new potent and selective σ2 receptor ligands.

Potholing of the hydrophobic heme oxygenase-1 western region for the search of potent and selective imidazole-based inhibitors

Here we report the design, synthesis, and molecular modeling of new potent and selective imidazole-based HO-1 inhibitors in which the imidazole nucleus and the hydrophobic groups are linked by a phenylethanolic spacer. Most of the tested compounds showed a good inhibitor activity with IC50 values in the low micromolar range, with two of them (1b and 1j) exhibiting also high selectivity toward HO-2. These results were obtained by the idea of potholing the entire volume of the principal hydrophobic western region with an appropriate ligand volume. Molecular modeling studies showed that these molecules bind to the HO-1 in the consolidated fashion where the imidazolyl moiety coordinates the heme iron while the aromatic groups are stabilized by hydrophobic interaction in the western region of the binding pocket. Finally, the synthesized compounds were analyzed for in silico ADME-Tox properties to establish oral drug-like behavior and showed satisfactory results.

Identification of Potentially Potent Heme Oxygenase 1 Inhibitors through 3D-QSAR Coupled to Scaffold-Hopping Analysis

A 3D quantitative structure–activity relationship (3D‐QSAR) model for predicting the activity of heme oxygenase 1 (HO‐1) inhibitors was constructed with the aim of providing a useful tool for the identification, design, and optimization of novel HO‐1 inhibitors. The model was built using a set of 222 HO‐1 inhibitors recovered from the Heme Oxygenase Database (HemeOxDB) and developed with the software Forge. The present model showed high statistical quality, as confirmed by its robust predictive potential and satisfactory descriptive capability. The drawn‐up 3D map enables prompt visual comprehension of the electrostatic, hydrophobic, and shaping features underlying the interactions with HO‐1 inhibitors. A theoretical approach for the generation of new lead compounds was performed by means of scaffold‐hopping analysis. For the first time, a 3D‐QSAR model is reported for this target, and was built with a number of chemically diverse HO‐1 inhibitors; the model also accounts well for individual ligand affinities. The new model contains all of the inhibitors published to date with high potency toward the selected target and contains a complete pharmacophore description of the binding cavity of HO‐1. These features will ensure application in accelerating the identification of new potent and selective HO‐1 inhibitors.

Novel Structural Insight into Inhibitors of Heme Oxygenase-1 (HO-1) by New Imidazole-Based Compounds: Biochemical and In Vitro Anticancer Activity Evaluation

In this paper, the design, synthesis, and molecular modeling of a new azole-based HO-1 inhibitors was reported, using compound 1 as a lead compound, in which an imidazole moiety is linked to a hydrophobic group by means of an ethanolic spacer. The tested compounds showed a good inhibitor activity and possessed IC50 values in the micromolar range. These results were obtained by targeting the hydrophobic western region. Molecular modeling studies confirmed a consolidated binding mode in which the nitrogen of the imidazolyl moiety coordinated the heme ferrous iron, meanwhile the hydrophobic groups were located in the western region of HO-1 binding pocket. Moreover, the new compounds were screened for in silico ADME-Tox properties to predict drug-like behavior with convincing results. Finally, the in vitro antitumor activity profile of compound 1 was investigated in different cancer cell lines and nanomicellar formulation was synthesized with the aim of improving compound’s 1 water solubility. Finally, compound 1 was tested in melanoma cells in combination with doxorubicin showing interesting synergic activity.

The hexameric resorcinarene capsule as an artificial enzyme: ruling the regio and stereochemistry of a 1,3-dipolar cycloaddition between nitrones and unsaturated aldehydes

When a 1,3-dipolar cycloaddition between nitrones and α,β-unsaturated aldehydes catalyzed by L-proline derivatives takes place inside the hexameric resorcin[4]arene capsule the products are obtained in higher yields and selectivity, with respect to the reaction in bulk solution. The 4-formyl regioisomers were obtained preferentially, with an excellent preference for the endo-diastereoisomers and with moderate to good enantioselectivities. An extended in silico study was conducted to rationalize the observed outcome and to investigate the equilibria between the reagents outside and inside the capsule.