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Caffeoylquinic acids (CQAs) are nutraceutical polyphenols highly represented in natural sources, including artichoke waste (AW). In this study a colorimetric method for rapid and sustainable detection of a 5-CQA isomer (Chlorogenic acid) in AW extract was developed by using alkaline Tris buffer (10 mmol L -1 , pH 9) to generate a yellow color associated with 5- to 3-CQA isomerization reaction, as suggested by NMR and MS analyses. The strong absorbance at 360 nm was followed by standard UV-Vis methodology. The colorimetric assay was exploited for detection of 5-CQA into leaf extract from artichoke, obtaining a value of 15.2 ± 0.3 μg/mg of dry extract, in agreement with HPLC analysis (14.3 ± 0.7 μg/mg, 106 ± 2 % recovery) used as validation technique, with excellent linear correlation and precision (R 2  = 0.9996, av RSD% = 3.2 %). The method is fast and selective, offering a valuable tool for nutraceuticals identification and food waste valorization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

A rapid and reliable evaluation of the aqueous solubility of small molecules is a hot topic for the scientific community and represents a field of particular interest in drug discovery. In fact, aqueous solubility significantly impacts various aspects that collectively influence a drug's overall pharmacokinetics, including absorption, distribution and metabolism. For this reason, in silico approaches that provide fast and cost-effective solubility predictions, can serve as invaluable tools in the early stages of drug development. Although additional molecular features should be considered, accurate solubility predictions can help medicinal chemists rationally planning the synthesis of compounds more likely to exhibit desirable pharmacokinetic properties and in selecting the most promising candidates for further biological testing (e.g., cellular assays) from an initial pool of hit compounds with detected preliminary bioactivity. In this context, we herein report the development and evaluation of WaSPred, our AI-based water solubility predictor for small molecules. WaSPred not only showed high reliability in water solubility predictions performed on structurally heterogeneous compounds, belonging to multiple external datasets, but also demonstrated superior performance compared to a set of other commonly used water solubility predictors, thus confirming its state-of the-art robustness and its usefulness as an in silico approach for water solubility evaluations.., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We present a new computational approach, named Watermelon , designed for the development of pharmacophore models based on receptor structures. The methodology involves the sampling of potential hotspots for ligand interactions within a protein target's binding site, utilising molecular fragments as probes. By employing docking and molecular dynamics (MD) simulations, the most significant interactions formed by these probes within distinct regions of the binding site are identified. These interactions are subsequently transformed into pharmacophore features that delineates key anchoring sites for potential ligands. The reliability of the approach was experimentally validated using the monoacylglycerol lipase (MAGL) enzyme. The generated pharmacophore model captured features representing ligand-MAGL interactions observed in various X-ray co-crystal structures and was employed to screen a database of commercially available compounds, in combination with consensus docking and MD simulations. The screening successfully identified two new MAGL inhibitors with micromolar potency, thus confirming the reliability of the Watermelon approach.

This study reports a comparative analysis of the polyphenolic composition and nutraceutical properties of different olive mill wastewater (OMWW) and corresponding extra virgin olive oil (EVOO) extracts. Specifically, four OMWWs and corresponding EVOOs from cultivars Frantoio (A) and Leccino (B) obtained from different crushing seasons (early-stage (A1 and B1) and later-stage (A2 and B2)) were analyzed. Employing HPLC-DAD and LC-MS methods, the primary polyphenol content was identified and quantified. Overall, OMWW extracts showed a greater polyphenolic content compared to corresponding EVOO extracts, with OMWW B1 displaying the highest levels of polyphenols. The antiradical properties of extracts towards radical species (DPPH, ABTS, O 2 - , and HOCl - ) were demonstrated in vitro, revealing a correlation with polyphenolic content. In fact, OMWW B1 and B2 demonstrated the strongest antiradical activity. Exploring nutraceutical properties of OMWWs, the intestinal permeation of the main polyphenols in a co-culture model (Caco-2 and HT29-MTX cell lines) was assessed, with tyrosol achieving a permeation of almost 60%. Furthermore, the involvement in the inflammation process has been evaluated in cell studies on THP1-derived macrophages by immunocytochemistry, demonstrating that OMWW B1 may exert an anti-inflammatory effect by modulating specific phenotype expression on macrophages. In conclusion, this study provides evidence supporting the reuse of OMWWs as a source of polyphenols with nutraceutical properties.

Background: ADAM17 is a metalloprotease implicated in the proteolysis of angiotensin-converting enzyme 2 (ACE2), known to play a critical role in the entry and spread of SARS-CoV-2. In this context, ADAM17 results as a potential novel target for controlling SARS-CoV-2 infection., Methods: In this study, we investigated the impact on ACE2 surface expression and the antiviral efficacy against SARS-CoV-2 infection of the selective ADAM17 inhibitor JG26 and its dimeric (compound 1) and glycoconjugate (compound 2) derivatives using Calu-3 human lung cells., Results: None of the compounds exhibited cytotoxic effects on Calu-3 cells up to a concentration of 25 µM. Treatment with JG26 resulted in partial inhibition of both ACE2 receptor shedding and SARS-CoV-2 infection, followed by compound 1., Conclusion: JG26, an ADAM17 inhibitor, demonstrated promising antiviral activity against SARS-CoV-2 infection, likely attributed to reduced sACE2 availability, thus limiting viral dissemination., (© 2024. The Author(s).)

Neuroinflammation is a critical aspect of various neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. This study investigates the anti-neuroinflammatory properties of oleocanthal and its oxidation product, oleocanthalic acid, using the BV-2 cell line activated with lipopolysaccharide. Our findings revealed that oleocanthal significantly inhibited the production of pro-inflammatory cytokines and reduced the expression of inflammatory genes, counteracted oxidative stress induced by lipopolysaccharide, and increased cell phagocytic activity. Conversely, oleocanthalic acid was not able to counteract lipopolysaccharide-induced activation. The docking analysis revealed a plausible interaction of oleocanthal, with both CD14 and MD-2 leading to a potential interference with TLR4 signaling. Since our data show that oleocanthal only partially reduces the lipopolysaccharide-induced activation of NF-kB, its action as a TLR4 antagonist alone cannot explain its remarkable effect against neuroinflammation. Proteomic analysis revealed that oleocanthal counteracts the LPS modulation of 31 proteins, including significant targets such as gelsolin, clathrin, ACOD1, and four different isoforms of 14-3-3 protein, indicating new potential molecular targets of the compound. In conclusion, oleocanthal, but not oleocanthalic acid, mitigates neuroinflammation through multiple mechanisms, highlighting a pleiotropic action that is particularly important in the context of neurodegeneration.

The proteolytic activity of the enzyme ADAMTS7 was recently shown to enhance the progression of atherosclerosis, in line with human genetic findings suggesting that ADAMTS7 has a role in the pathophysiology of coronary heart disease. Targeting the active site of ADAMTS7 with a small molecule inhibitor, therefore, has therapeutic potential. Here, we report the design and synthesis of a novel hydroxamate-based arylsulfonamide that is a potent and selective ADAMTS7 inhibitor. In silico studies guided the hit optimization process aiming to improve selectivity of the previously reported (non-selective) inhibitor EDV33. Our lead compound is a p -trifluoromethyl biphenyl sulfonamide, which displayed a 12-fold selectivity for ADAMTS7 ( K i = 9 nM) over ADAMTS5 ( K i = 110 nM) and an 8-fold increase in inhibition of ADAMTS7 compared to EDV33 ( K i = 70 nM). The substitutions switched selectivity and produced a new potent ADAMTS7 inhibitor that can be taken forward for further characterisation., Competing Interests: No potential conflict of interest was reported by the authors., (This journal is © The Royal Society of Chemistry.)

Extra virgin olive oil (EVOO) is a symbol of the Mediterranean diet, constituting its primary source of fat. The beneficial effect of EVOO is strictly related to the presence of fatty acids and polyphenols, bioactive compounds endowed with nutraceutical properties. Among EVOO polyphenols, lignans possess a steroid-like chemical structure and are part of the phytoestrogen family, which is renowned for its health properties. The natural lignans (+)-pinoresinol and 1-acetoxypinoresinol (1-AP) are commonly present in olives and in EVOO. Although (+)-pinoresinol is found in different edible plants, such as flaxseed, beans, whole-grain cereals, sesame seeds, and certain vegetables and fruit, 1-AP was exclusively identified in olives in 2000. So far, the scientific literature has extensively covered different aspects of (+)-pinoresinol, including its isolation and nutraceutical properties. In contrast, less is known about the olive lignan 1-AP. Therefore, this review aimed to comprehensively evaluate the more important aspects of 1-AP, collecting all the literature from 2016 to the present, exploring its distribution in different cultivars, analytical isolation and purification, and nutraceutical properties.

The application of artificial intelligence and machine learning (ML) methods is becoming increasingly popular in computational toxicology and drug design; it is considered as a promising solution for assessing the safety profile of compounds, particularly in lead optimization and ADMET studies, and to meet the principles of the 3Rs, which calls for the replacement, reduction, and refinement of animal testing. In this context, we herein present the development of VenomPred 2.0 (http://www.mmvsl.it/wp/venompred2/), the new and improved version of our free of charge web tool for toxicological predictions, which now represents a powerful web-based platform for multifaceted and human-interpretable in silico toxicity profiling of chemicals. VenomPred 2.0 presents an extended set of toxicity endpoints (androgenicity, skin irritation, eye irritation, and acute oral toxicity, in addition to the already available carcinogenicity, mutagenicity, hepatotoxicity, and estrogenicity) that can be evaluated through an exhaustive consensus prediction strategy based on multiple ML models. Moreover, we also implemented a new utility based on the Shapley Additive exPlanations (SHAP) method that allows human interpretable toxicological profiling of small molecules, highlighting the features that strongly contribute to the toxicological predictions in order to derive structural toxicophores.

The degradation of the endocannabinoid 2-arachidonoylglycerol is mediated by the enzyme monoacylglycerol lipase (MAGL), thus generating arachidonic acid, the precursor of prostaglandins and other pro-inflammatory mediators. MAGL also contributes to the hydrolysis of monoacylglycerols into glycerol and fatty acids in peripheral body districts, which may act as pro-tumorigenic signals. For this reason, MAGL inhibitors have been considered as interesting therapeutic agents for their anti-nociceptive, anti-inflammatory, antioxidant and anti-cancer properties. So far, only a limited series of reversible MAGL inhibitors, which are devoid of side effects shown by irreversible inhibitors in animal models, have been reported. Here we optimized a class of benzylpiperidine and benzylpiperazine-based compounds for a reversible MAGL inhibition. The best MAGL inhibitors of this class, compounds 28 and 29, showed a very good inhibition potency, both on the isolated enzyme and in U937 cells, as confirmed by molecular modeling studies that predicted their binding mode into the MAGL active site. Both compounds are characterized by a high selectivity for MAGL versus other serine hydrolases including enzymes of the endocannabinoid system, as confirmed by ABPP experiments in mouse brain membranes. Moreover, very good properties concerning ADME parameters and low in vivo toxicity have been observed for both compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Glycogen synthase kinase-3 beta (GSK3β) is a serine/threonine kinase that plays key roles in glycogen metabolism, Wnt/β-catenin signaling cascade, synaptic modulation, and multiple autophagy-related signaling pathways. GSK3β is an attractive target for drug discovery since its aberrant activity is involved in the development of neurodegenerative diseases such as Alzheimer's and Parkinson's disease. In the present study, multiple machine learning models aimed at identifying novel GSK3β inhibitors were developed and evaluated for their predictive reliability. The most powerful models were combined in a consensus approach, which was used to screen about 2 million commercial compounds. Our consensus machine learning-based virtual screening led to the identification of compounds G1 and G4 , which showed inhibitory activity against GSK3β in the low-micromolar and sub-micromolar range, respectively. These results demonstrated the reliability of our virtual screening approach. Moreover, docking and molecular dynamics simulation studies were employed for predicting reliable binding modes for G1 and G4 , which represent two valuable starting points for future hit-to-lead and lead optimization studies.

h RPE65 is a fundamental enzyme of the retinoid visual cycle, and many missense mutations affecting its expression or function are associated with a wide range of diseases. Many h RPE65 missense mutations lack a clear pathogenicity classification or are labelled as VUS. In this context, we recently developed a protocol based on µs-long molecular dynamics simulations to study the potential pathogenic effect of h RPE65 missense mutations. In the present work, the structure-based protocol was integrated with a h RPE65-tailored consensus bioinformatics strategy, named ConPath, that showed high performance in predicting known pathogenic/benign h RPE65 missense mutations. The combined strategy was used to perform a multi-level evaluation of the potential pathogenicity of 13 different h RPE65 VUS, which were classified based on their likelihood of pathogenic effect. The obtained results provide information that may support the reclassification of these VUS and help clinicians evaluate the eligibility for gene therapy of patients diagnosed with such variants.

Background: Agrifood waste products are often considered rich sources of bioactive compounds that can be conveniently recovered. Due to these peculiar characteristics, the study of these waste products is attracting great interest in nutraceutical research. Olive mill wastewaters (OMWWs) are generated by extra virgin olive oil (EVOO) production, and they pose environmental challenges due to their disposal. This study aimed to characterize the polyphenolic profile and to evaluate the nutraceutical properties of OMWW extracts from two Tuscan olive cultivars, Leccino (CL) and Frantoio (CF), collected during different time points in EVOO production., Method: After a liquid-liquid extraction, the HPLC and LC-MS/MS analysis of OMWW extracts confirmed the presence of 18 polyphenolic compounds., Results: The polyphenol composition varied between the cultivars and during maturation stages. Notably, oleacein was detected at remarkably high levels in CL1 and CF1 extracts (314.628 ± 19.535 and 227.273 ± 3.974 μg/mg, respectively). All samples demonstrated scavenging effects on free radicals (DPPH and ABTS assays) and an anti-inflammatory potential by inhibiting cyclooxygenase (COX) enzymes., Conclusions: This study highlights the nutraceutical potential of OMWW extracts, emphasizing their antioxidant, antiradical, and anti-inflammatory activities. The results demonstrate the influence of olive cultivar, maturation stage, and extraction process on the polyphenolic composition and the bioactivity of OMWW extracts. These findings support a more profitable reuse of OMWW as an innovative, renewable, and low-cost source of dietary polyphenols with potential applications as functional ingredients in the development of dietary supplements, as well as in the pharmaceutical and cosmetics industries.

Here, we present MolBook UNIPI, freely available and user-friendly software specifically designed for medicinal chemists as a powerful tool for the easy management of virtual libraries of chemical compounds. With MolBook UNIPI, it is possible to create, store, handle, and share molecular databases in a very simple and intuitive way. The software allows users to rapidly generate libraries of bioactive ligands, building blocks, or commercial compounds by either manually creating single molecules or automatically importing compounds from public databases and pre-existing libraries. MolBook UNIPI databases can be enriched with all kinds of data and can be filtered based on molecular structures or properties, allowing the desired molecules, along with their structures and features, to be easily accessible in just a few clicks. Moreover, new molecular properties and potential toxicological effects of compounds can be rapidly and reliably predicted. Notably, all of these functions can be easily mastered even by inexperienced users, with no prior cheminformatics knowledge or programming skills, which makes MolBook UNIPI an invaluable tool for medicinal chemists. MolBook UNIPI can be downloaded free of charge from the project web page https://molbook.farm.unipi.it/.

(1) Background: In recent years, numerous studies have highlighted the beneficial effects of extra virgin olive oil (EVOO) as an active ingredient against chronic diseases. The properties of EVOO are due to its peculiar composition, mainly to its rich content of polyphenols. In fact, polyphenols may contribute to counteract oxidative stress, which often accompanies chronic diseases. In this work, the antioxidant effects of high-value polyphenol oleocanthal (OC) and its main metabolites, tyrosol (Tyr) and oleocanthalic acid (OA), respectively, have been investigated along with their impact on cell viability. (2) Methods: OC, Tyr, and OA have been evaluated regarding antiradical properties in term of scavenging capacity towards biologically relevant reactive species, including O 2 ●- , HOCl, and ROO ● , as well as their antioxidant/antiradical capacity (FRAP, DPPH ● , ABTS ●+ ). Moreover, the ability to permeate the intestinal membrane was assessed by an intestinal co-culture model composed by Caco-2 and HT29-MTX cell lines. (3) Results: The capacity of OC and Tyr as radical oxygen species (ROS) scavengers, particularly regarding HOCl and O 2 ●- , was clearly demonstrated. Furthermore, the ability to permeate the intestinal co-culture model was plainly proved by the good permeations (>50%) achieved by all compounds. (4) Conclusions: OC, OA, and Tyr revealed promising properties against oxidative diseases.

(1) Background: Nowadays, the health-promoting properties of extra virgin olive oil (EVOO), including the antioxidant and anti-inflammatory actions, are well recognized and mainly attributed to the different polyphenols, such as oleocanthal and oleacein. In EVOO production, olive leaves represent a high value by-product, showing a wide spectrum of beneficial effects due to the presence of polyphenols, especially oleuropein. Here we report the study of olive leaf extract (OLE)-enriched EVOO extracts, obtained by adding different percentages of OLE to EVOO in order to ameliorate their nutraceutical activities. (2) Methods: The polyphenolic content of the EVOO/OLE extracts was analyzed by HPLC and the Folin-Ciocalteau assay. For further biological testing, an 8% OLE-enriched EVOO extract was chosen. Therefore, antioxidant effects were evaluated by three different methods (DPPH, ABTS, and FRAP), and the anti-inflammatory properties were assessed in terms of cyclooxygenase activity inhibition. (3) Results: The antioxidant and anti-inflammatory profiles of the new EVOO/OLE extract are significantly improved compared to those of EVOO extract; (4) Conclusions: The combination of OLE and EVOO extract can lead to an extract enriched in terms of bioactive polyphenols and endowed with better biological properties than the singular EVOO extract. Therefore, it may represent a new complement in the nutraceutical field.

Liver fibrosis is the result of a chronic pathological condition caused by the activation of hepatic stellate cells (HSCs), which induces the excessive deposition of extracellular matrix. Fibrogenesis is sustained by an exaggerated production of reactive oxidative species (ROS) by NADPH oxidases (NOXs), which are overactivated in hepatic inflammation. In this study, we investigated the antifibrotic properties of two phenolic compounds of natural origin, tyrosol (Tyr) and hydroxytyrosol (HTyr), known for their antioxidant and anti-inflammatory effects. We assessed Tyr and HTyr antifibrotic and antioxidant activity both in vitro, by a co-culture of LX2, HepG2 and THP1-derived Mϕ macrophages, set up to simulate the hepatic microenvironment, and in vivo, in a mouse model of liver fibrosis obtained by carbon tetrachloride treatment. We evaluated the mRNA and protein expression of profibrotic and oxidative markers (α-SMA, COL1A1, NOX1/4) by qPCR and/or immunocytochemistry or immunohistochemistry. The expression of selected miRNAs in mouse livers were measured by qPCR. Tyr and HTyr reduces fibrogenesis in vitro and in vivo, by downregulating all fibrotic markers. Notably, they also modulated oxidative stress by restoring the physiological levels of NOX1 and NOX4. In vivo, this effect was accompanied by a transcriptional regulation of inflammatory genes and of 2 miRNAs involved in the control of oxidative stress damage (miR-181-5p and miR-29b-3p). In conclusion, Tyr and HTyr exert antifibrotic and anti-inflammatory effects in preclinical in vitro and in vivo models of liver fibrosis, by modulating hepatic oxidative stress, representing promising candidates for further development., Competing Interests: Conflict of interest statement The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

PIN1 is considered as a therapeutic target for a wide variety of tumours. However, most of known inhibitors are devoid of cellular activity despite their good enzyme inhibitory profile. Hence, the lack of effective compounds for the clinic makes the identification of novel PIN1 inhibitors a hot topic in the medicinal chemistry field. In this work, we reported a virtual screening study for the identification of new promising PIN1 inhibitors. A receptor-based procedure was applied to screen different chemical databases of commercial compounds. Based on the whole workflow, two compounds were selected and biologically evaluated. Both ligands, compounds VS1 and VS2 , showed a good enzyme inhibitory activity and VS2 also demonstrated a promising antitumoral activity in ovarian cancer cells. These results confirmed the reliability of our in silico protocol and provided a structurally novel ligand as a valuable starting point for the development of new PIN1 inhibitors.

The human retinal pigment epithelium-specific 65-kDa protein ( h RPE65) plays a crucial role within the retinoid visual cycle and several mutations affecting either its expression level or its enzymatic function are associated with inherited retinal diseases such as Retinitis Pigmentosa. The gene therapy product voretigene neparvovec (Luxturna) has been recently approved for treating hereditary retinal dystrophies; however, the treatment is currently accessible only to patients presenting confirmed biallelic mutations that severely impair h RPE65 function, and many reported h RPE65 missense mutations lack sufficient evidences for proving their pathogenicity. In this context, we developed a computational approach aimed at evaluating the potential pathogenic effect of h RPE65 missense variants located on the dimerisation domain of the protein. The protocol evaluates how mutations may affect folding and conformation stability of this protein region, potentially helping clinicians to evaluate the eligibility for gene therapy of patients diagnosed with this type of h RPE65 variant of uncertain significance.

Polyhydroxyalkanoates (PHAs) are a family of biopolyesters synthesized by various microorganisms. Due to their biocompatibility and biodegradation, PHAs have been proposed for biomedical applications, including tissue engineering scaffolds. Olive leaf extract (OLE) can be obtained from agri-food biowaste and is a source of polyphenols with remarkable antioxidant properties. This study aimed at incorporating OLE inside poly(hydroxybutyrate-co-hydroxyvalerate) (PHBHV) fibers via electrospinning to obtain bioactive bio-based blends that are useful in wound healing. PHBHV/OLE electrospun fibers with a size of 1.29 ± 0.34 µm were obtained. Fourier transform infrared chemical analysis showed a uniform surface distribution of hydrophilic -OH groups, confirming the presence of OLE in the electrospun fibers. The main OLE phenols were released from the fibers within 6 days. The biodegradation of the scaffolds in phosphate buffered saline was investigated, demonstrating an adequate stability in the presence of metalloproteinase 9 (MMP-9), an enzyme produced in chronic wounds. The scaffolds were preliminarily tested in vitro with HFFF2 fibroblasts and HaCaT keratinocytes, suggesting adequate cytocompatibility. PHBHV/OLE fiber meshes hold promising features for wound healing, including the treatment of ulcers, due to the long period of durability in an inflamed tissue environment and adequate cytocompatibility.

Cyclin-dependent kinase 5 (Cdk5) is an atypical proline-directed serine/threonine protein kinase well-characterized for its role in the central nervous system rather than in the cell cycle. Indeed, its dysregulation has been strongly implicated in the progression of synaptic dysfunction and neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), and also in the development and progression of a variety of cancers. For this reason, Cdk5 is considered as a promising target for drug design, and the discovery of novel small-molecule Cdk5 inhibitors is of great interest in the medicinal chemistry field. In this context, we employed a machine learning-based virtual screening protocol with subsequent molecular docking, molecular dynamics simulations and binding free energy evaluations. Our virtual screening studies resulted in the identification of two novel Cdk5 inhibitors, highlighting an experimental hit rate of 50% and thus validating the reliability of the in silico workflow. Both identified ligands, compounds CPD1 and CPD4 , showed a promising enzyme inhibitory activity and CPD1 also demonstrated a remarkable antiproliferative activity in ovarian and colon cancer cells. These ligands represent a valuable starting point for structure-based hit-optimization studies aimed at identifying new potent Cdk5 inhibitors.

A growing body of evidence underlines the crucial role of GPR55 in physiological and pathological conditions. In fact, GPR55 has recently emerged as a therapeutic target for several diseases, including cancer and neurodegenerative and metabolic disorders. Several lines of evidence highlight GPR55's involvement in the regulation of microglia-mediated neuroinflammation, although the exact molecular mechanism has not been yet elucidated. Nevertheless, there are only a limited number of selective GPR55 ligands reported in the literature. In this work, we designed and synthesized a series of novel GPR55 ligands based on the 3-benzylquinolin-2(1 H )-one scaffold, some of which showed excellent binding properties (with K i values in the low nanomolar range) and almost complete selectivity over cannabinoid receptors. The full agonist profile of all the new derivatives was assessed using the p-ERK activation assay and a computational study was conducted to predict the key interactions with the binding site of the receptor. Our data outline a preliminary structure-activity relationship (SAR) for this class of molecules at GPR55. Some of our compounds are among the most potent GPR55 agonists developed to date and could be useful as tools to validate this receptor as a therapeutic target.

Monoacylglycerol lipase (MAGL) is the enzyme responsible for the metabolism of 2-arachidonoylglycerol in the brain and the hydrolysis of peripheral monoacylglycerols. Many studies demonstrated beneficial effects deriving from MAGL inhibition for neurodegenerative diseases, inflammatory pathologies, and cancer. MAGL expression is increased in invasive tumors, furnishing free fatty acids as pro-tumorigenic signals and for tumor cell growth. Here, a new class of benzylpiperidine-based MAGL inhibitors was synthesized, leading to the identification of 13 , which showed potent reversible and selective MAGL inhibition. Associated with MAGL overexpression and the prognostic role in pancreatic cancer, derivative 13 showed antiproliferative activity and apoptosis induction, as well as the ability to reduce cell migration in primary pancreatic cancer cultures, and displayed a synergistic interaction with the chemotherapeutic drug gemcitabine. These results suggest that the class of benzylpiperidine-based MAGL inhibitors have potential as a new class of therapeutic agents and MAGL could play a role in pancreatic cancer.

The health benefits of extra-virgin olive oil (EVOO) are strictly linked to the presence of phenolic compounds, which exhibit numerous nutraceutical properties. In EVOO, the most important class of phenolic compounds is represented by secoiridoids (oleacein and oleocanthal). EVOO is constantly subjected to degradation processes, including hydrolytic and oxidative reactions that influence its phenolic composition. In particular, the hydrolytic reactions determine the transformation of oleocanthal and oleacein into the corresponding phenyl-alcohols, tyrosol, and hydroxytyrosol. Furthermore, oleocanthal by oxidation processes can be converted to oleocanthalic acid. In this study, we evaluated the phenolic composition of three EVOO samples kept at different storage conditions for 15 months, focusing on the variation of oleocanthalic acid content. Specifically, the samples were stored at 4 °C in darkness and at 25 °C with light exposure. The results of our analyses highlighted that in EVOOs exposed to light and maintained at 25 °C, the degradation was more marked than in EVOO stored in dark and at 4 °C, due to the greater influence of external factors on storage conditions. Although chemical-physical characteristics of EVOOs are slightly different depending on provenience and treatment time, the results of this study reveal that storage conditions are fundamental to controlling phenol concentration.

The use of in silico toxicity prediction methods plays an important role in the selection of lead compounds and in ADMET studies since in vitro and in vivo methods are often limited by ethics, time, budget and other resources. In this context, we present our new web tool VenomPred, a user-friendly platform for evaluating the potential mutagenic, hepatotoxic, carcinogenic and estrogenic effects of small molecules. VenomPred platform employs several in-house Machine Learning (ML) models developed with datasets derived from VEGA QSAR, a software that includes a comprehensive collection of different toxicity models and has been used as a reference for building and evaluating our ML models. The results showed that our models achieved equal or better performance than those obtained with the reference models included in VEGA QSAR. In order to improve the predictive performance of our platform, we adopted a consensus approach combining the results of different ML models, which was able to predict chemical toxicity better than the single models. This improved method was thus implemented in the VenomPred platform, a freely accessible webserver that takes the SMILES (Simplified Molecular-Input Line-Entry System) strings of the compounds as input and sends the prediction results providing a probability score about their potential toxicity.

The development of cannabinoid receptor type-1 (CB1R) modulators has been implicated in multiple pathophysiological events ranging from memory deficits to neurodegenerative disorders among others, even if their central psychiatric side effects such as depression, anxiety, and suicidal tendencies, have limited their clinical use. Thus, the identification of ligands which selectively act on peripheral CB1Rs, is becoming more interesting. A recent study reported a class of peripheral CB1R selective antagonists, characterized by a 5-aryl substituted nicotinamide core. These derivatives have structural similarities with the biphenyl compounds, endowed with CB2R antagonist activity, previously synthesized by our research group. In this work we combined the pharmacophoric portion of both classes, in order to obtain novel CBR antagonists. Among the synthesized compounds rather unexpectedly two compounds of this series, C7 and C10, did not show the radioligand ([ 3 H]CP55940) displacement on CB1R but increased binding (∼ 150%), suggesting a possible allosteric behavior. Computational studies were performed to investigate the role of these compounds in CB1R modulation. The analysis of their binding poses in two different binding cavities of the CB1R surface, revealed a preferred interaction with the experimental binding site for negative allosteric modulators., (Copyright © 2021. Published by Elsevier B.V.)