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Background: The inhibition of PRC2, implicated in the pathogenesis of several tumors, can be a useful therapeutic strategy for cancer treatment. In the literature, two types of PRC2 modulators are reported: competitive inhibitors of S-adenosyl methionine binding to the catalytic subunit EZH2; and allosteric ligands that prevent the interaction of the trimethylated H3K27 lysine in histone 3 to the EED subunit. The lack of dual EZH2/EED modulators drove us to search for compounds capable of recognizing both domains. Materials & methods: This goal was pursued by combining pharmacophore- and docking-based virtual screening of the Multi-Target Ligand Chemotheca database. Prediction tools for absorption, distribution, metabolism and excretion and pan-assay interference compounds were also applied. Results: Finally, five 1,2,3-triazole derivatives were identified as promising dual EZH2/EED modulators. Conclusion: Our multistage screening protocol highlighted the great potential of Chemotheca for identifying polypharmacological agents.

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.

Multiple myeloma (MM) is an incurable hematological malignancy driven by several genetic and epigenetic alterations. The hyperactivation of the Polycomb repressive complex 2 (PRC2), a multi-subunit oncogenic histone methyltransferase, has been implicated in the pathogenesis of this malignancy. Upon protein-protein interaction (PPI) between the catalytic subunit EZH2 and EED, PRC2 primarily methylates lysine 27 of histone H3 (H3K27me3), thus modulating the chromatin structure and inducing transcriptional repression. Herein, we highlight a new mechanism of action that can contribute to explain the anti-tumor activity of hydroxychloroquine (HCQ), an anti-malaric agent also known as autophagy inhibitor. By structural studies, we demonstrate that HCQ inhibits the allosteric binding of PRC2 to EED within the H3K27me3-binding pocket, thus antagonizing the PRC2 catalytic activity. In silico results are compatible with the significant reduction of the H3K27me3 levels in MM cells exerted by HCQ. Overall, these findings disclose a novel epigenetic activity of HCQ with potential implications for its clinical repositioning.

This chapter focuses on computational techniques for identifying and optimizing lead molecules, with a special emphasis on natural compounds. A number of case studies have been specifically discussed, such as the case of the naphthyridine scaffold, discovered through a structure-based virtual screening (SBVS) and proposed as the starting point for further lead optimization process, to enhance its telomeric RNA selectivity. Another example is the case of Liphagal, a tetracyclic meroterpenoid extracted fromAka coralliphaga, known as PI3Kα inhibitor, provide an evidence for the design of new active congeners against PI3Kα using molecular dynamics (MD) simulations. These are only two of the numerous examples of the computational techniques’ powerful in drug design and drug discovery fields. Finally, the design of drugs that can simultaneously interact with multiple targets as a promising approach for treating complicated diseases has been reported. An example of polypharmacological agents are the compounds extracted from mushrooms identified by means of molecular docking experiments. This chapter may be a useful manual of molecular modeling techniques used in the lead-optimization and lead identification processes.

It is well recognized that the non-canonical DNA structures known as G-quadruplexes (G4s) have a potential anticancer significance and several compounds have been discovered and evaluated as promising G4 binders with anticancer activity. Here, starting from a promising hit with an indolo-naphthyridine scaffold, a small series of five indolo-naphthyridine based derivatives have been designed and evaluated as G4-targeting compounds. FRET biophysical studies were performed on multiple DNA G4 structures, leading to the identification of a multi-target G4 stabilizer with a slight preference for the c-KIT1 and a good G4 over duplex selectivity. The good affinity of this compound against c-KIT1 G4 was also confirmed by SPR and MST experiments, while biological assays revealed its cytotoxic activity on tumour cells. Finally, Molecular Dynamics simulations helped to elucidate the stabilization effect of the selected compound against the c-KIT1 G4.

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.

Many bioactive agents have been extracted from plants or belong to functional foods and have been considered in the treatment of serious and multifactorial diseases, such as cancer. In particular, this review is focused on the anti-cancer properties owned by several natural products typically from the Mediterranean area. In some regions of the South of Italy, a lower cancer incidence has been observed. There is increasing evidence that adherence to a Mediterranean dietary pattern correlates with reduced risk of several cancer types. This could be mainly attributed to the typical lifestyle aspects of the Mediterranean diet, such as high consumption of fruit and vegetables. In this review, the main natural products of the Mediterranean area are discussed, with particular attention on their anti-cancer properties endowed with multi-target profiles.

A number of compounds targeting different processes of the Human Immunodeficiency Virus type 1 (HIV-1) life cycle have been developed in the continuing fight against AIDS. Coumarin-based molecules already proved to act as HIV-1 Protease (PR) or Integrase (IN) inhibitors and also to target HIV-1 reverse transcriptase (RT), blocking the DNA-dependent DNA-polymerase activity or the RNA-dependent DNA-polymerase activity working as common NNRTIs. In the present study, with the aim to exploit a coumarin-based scaffold to achieve the inhibition of multiple viral coded enzymatic functions, novel 4-hydroxy-2H, 5H-pyrano (3, 2-c) chromene-2, 5-dione derivatives were synthesized. The modeling studies calculated the theoretical binding affinity of the synthesized compounds on both HIV-1 IN and RT-associated Ribonuclease H (RNase H) active sites, which was confirmed by biological assays. Our results provide a basis for the identification of dual HIV-1 IN and RT RNase H inhibitors compounds.