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Eighteen new 1-N-substituted-3,5-diphenyl-2-pyrazoline derivatives have been synthesized and cyclooxygenase (COX-1 and COX-2) inhibitory activities have been evaluated. The results of these biological assays showed that all of new derivatives are not endowed with improved anti-inflammatory activity against COX-1, but some of them showed a good activity against COX-2. To evaluate the binding mode of the most significative compounds (2d, 2f, 2g and 2k) docking studies were carried out. These studies confirmed biological data, in fact these compounds were able to fit into the active site of COX-2.

An increasingly comprehension of the folding intermediate states of DNA G-quadruplexes (G4s) is currently an important scientific challenge, especially for the human telomeric (h-tel) G4s-forming sequences, characterized by a highly polymorphic nature. Despite the G-triplex conformation was proposed as one of the possible folding intermediates for the antiparallel and hybrid h-tel G4s, for the parallel h-tel topology with an all-anti guanine orientation, a vertical strand-slippage involving the G-triplets was proposed in previous works through microseconds-long standard molecular dynamics simulations (MDs). Here, in order to get further insights into the vertical strand-slippage and the folding intermediate states of the parallel h-tel G4s, we have carried out a Well-Tempered Metadynamics simulation (WT-MetaD), which allowed us to retrieve an ensemble of six G4s having two/G-tetrad conformations derived by the G-triplets vertical slippage. The insights highlighted in this work are aimed at rationalizing the mechanistic characterisation of the parallel h-tel G4 folding process.

SARS-CoV-2 entry in human cells is mediated by the interaction between the viral Spike protein and the human ACE2 receptor. This mechanism evolved from the ancestor bat coronavirus and is currently one of the main targets for antiviral strategies. However, there currently exist several Spike protein variants in the SARS-CoV-2 population as the result of mutations, and it is unclear if these variants may exert a specific effect on the affinity with ACE2 which, in turn, is also characterized by multiple alleles in the human population. In the current study, the GBPM analysis, originally developed for highlighting host-guest interaction features, has been applied to define the key amino acids responsible for the Spike/ACE2 molecular recognition, using four different crystallographic structures. Then, we intersected these structural results with the current mutational status, based on more than 295,000 sequenced cases, in the SARS-CoV-2 population. We identified several Spike mutations interacting with ACE2 and mutated in at least 20 distinct patients: S477N, N439K, N501Y, Y453F, E484K, K417N, S477I and G476S. Among these, mutation N501Y in particular is one of the events characterizing SARS-CoV-2 lineage B.1.1.7, which has recently risen in frequency in Europe. We also identified five ACE2 rare variants that may affect interaction with Spike and susceptibility to infection: S19P, E37K, M82I, E329G and G352V. Communicated by Ramaswamy H. Sarma

Essential oils (EOs) are popular in aromatherapy, a branch of alternative medicine that claims their curative effects. Moreover, several studies reported EOs as potential anti-cancer agents by inducing apoptosis in different cancer cell models. In this study, we have considered EOs as a potential resource of new kinase inhibitors with a polypharmacological profile. On the other hand, computational methods offer the possibility to predict the theoretical activity profile of ligands, discovering dangerous off-targets and/or synergistic effects due to the potential multi-target action. With this aim, we performed a Structure-Based Virtual Screening (SBVS) against X-ray models of several protein kinases selected from the Protein Data Bank (PDB) by using a chemoinformatics database of EOs. By evaluating theoretical binding affinity, 13 molecules were detected among EOs as new potential kinase inhibitors with a multi-target profile. The two compounds with higher percentages in the EOs were studied more in depth by means Induced Fit Docking (IFD) protocol, in order to better predict their binding modes taking into account also structural changes in the receptor. Finally, given its good binding affinity towards five different kinases, cinnamyl cinnamate was biologically tested on different cell lines with the aim to verify the antiproliferative activity. Thus, this work represents a starting point for the optimization of the most promising EOs structure as kinase inhibitors with multi-target features.

The human Carbonic anhydrases (hCA) VA and VB play a key role in ureagenesis, gluconeogenesis, lipogenesis and in the metabolism regulation, thus representing highly popular drug targets. Albeit several hCA inhibitors have been designed and are currently in clinical use, serious drug interactions have been reported due to their poor selectivity. In this perspective, the drug repurposing approach could be a useful tool in order to investigate the drug promiscuity/polypharmacology profile. In this study, virtual screening techniques and in vitro assays were combined to identify novel selective hCA VA inhibitors from among around 94000 compounds. The docking analysis highlighted 12 promising best hits, biologically characterized in terms of their hCA VA inhibitory activity. Interestingly, among them, the anticancer agents fludarabine and lenvatinib and the antiepileptic rufinamide were able to selectively inhibit the enzyme activity in the micromolar range, while a pyrido-indole derivative, the homovanillic acid sulfate and the desacetyl metabolite of the antibacterial cephapirin in the nanomolar range.

This paper focuses on advanced computational techniques for identifying and optimizing lead molecules, such as metadynamics and a novel dynamic 3D pharmacophore analysis method called Dynophores. In this paper, the first application of the funnel metadynamics of the Berberine binding to G-quadruplex DNA is depicted, disclosing hints for drug design, in particular clarifying water’s role and suggesting the design of derivatives able to replace the solvent-mediated interactions between ligand and DNA to achieve more potent and selective activity. Secondly, the novel dynamic pharmacophore approach is an extension of the classic 3D pharmacophores, with statistical and sequential information about the conformational flexibility of a molecular system derived from molecular dynamics (MD) simulations.

In this work we report a parallel application of both docking- and shape-based virtual screening (VS) methods, followed by Molecular Dynamics simulations (MDs), for discovering new compounds able to inhibit the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) RNA-dependent DNA polymerase activity. Specifically, we screened more than 143000 natural compounds commercially available in the ZINC database against the best five RT crystallographic models, taking into account the five approved NNRTIs as query compounds. As a result, 20 hit molecules were selected and tested on biochemical assays for the inhibition of the RNA dependent DNA polymerase RT function and, among them, an indoline pyrrolidine (hit1), an indonyl piperazine (hit2) and an indolyl indolinone (hit3) derivatives were identified as novel non-nucleoside RT inhibitors in the low micromolar range.

Alteration of nutritional habits play an essential role on the risk of developing Metabolic Syndrome (MetS). Several epidemiological studies have shown that assuming diets rich of foods included in the Mediterranean diet (MetDiet) pattern like, such as olive oil, nuts, fruit, fiber, vegetables, wine and grain cereals has protective effects on the different risk factors characterizing the MetS. The beneficial effects of the MetDiet in the MetS are mainly due to the antioxidant and anti-inflammatory properties of the most abundant phytochemical components of such foods as polyphenols like resveratrol and oleuropein, allyl sulfides, ellagic acid, mono- and poly-unsaturated fatty acids (MUFA and PUFA), tocopherols and flavonoids like quercetin, which have shown positive results in the prevention of cardiovascular diseases (CVDs), with related risk factors, like hypertension, hypercholesterolemia and obesity. In this review, we highlighted the multi-target activities of the bioactive components contained in some foods typical of the Mediterranean area like olive oil, onion, liquorice, rosemary, oregano, hazelnut, pistachio, "Melannurca" apple, red wine, hot pepper, Citrus sp. fruits, saffron and garlic, with particular focus on their impact on health outcomes in relation to MetS main key factors, such as insulin resistance (IR) and type 2 diabetes mellitus (T2DM), endothelial dysfunctions, inflammatory response, oxidative stress and dyslipidaemic and hypercholesterolemic effects.

3-Substituted 6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepines and related compounds were synthesized as central benzodiazepine receptor (CBR) ligands. Most of the compounds showed high affinity for bovine and human CBR, their K(i) values spanning from the low nanomolar to the submicromolar range. In particular, imidazoester 5f was able to promote a massive flow of (36)Cl(-) in rat cerebrocortical synaptoneurosomes overlapping its efficacy profile with that of a typical full agonist. Compound 5f was then examined in mice for its pharmacological effects where it proved to be a safe anxiolytic agent devoid of the unpleasant myorelaxant and amnesic effects of the classical 1,4-benzodiazepines. Moreover, the selectivity of some selected compounds has been assessed in recombinant α(1)β(2)γ(2)L, α(2)β(1)γ(2)L, and α(5)β(2)γ(2)L human GABA(A) receptors. Finally, some compounds were submitted to molecular docking calculations along with molecular dynamics simulations in the Cromer's GABA(A) homology model.

Candida rugosa lipase crude preparations (CRL) catalyse the regioselective acylation of methyl 6-O-trytil β-d-glucopyranoside in organic solvents, using vinyl acetate as acyl donor. The ratio of the two products formed, namely methyl 2-O acetyl 6-O-trytil β-d-glucopyranoside and methyl 3-O acetyl 6-O-trytil β-d-glucopyranoside was found to be markedly affected by the nature of the reaction medium. In hydrophobic solvents values up to 80% of the monoacetylated product in position C-3 were obtained compared to less than 30% in solvents with low hydrophobicity. Computational studies were carried out to simulate the interactions between methyl 6-O-trytil β-d-glucopyranoside and both CRL and the solvents, in order to rationalize the experimental results. © 2007 Elsevier B.V. All rights reserved.

Il contributo analizza i maggiori costi che le strutture sanitarie pubbliche della Regione Molise, situate in territori di montagna, devono sopportare per l'erogazione delle prestazioni sanitarie. L'analisi empirica svolta attraverso l'applicazione degli strumenti di contabilità analitica e di controllo di gestione ha evidenziato l'erogazione di prestazioni sanitarie in territori montuosi anche in condizioni di mancata efficienza, efficacia ed economicità.